IL-17A activity inhibitors and their applications

Abstract

An object of the present invention is to provide a small molecule compound (IL-17 activity inhibitor) having a more potent inhibitory effect on IL-17 activity than conventional compounds. The IL-17RA inhibitor of the present invention is, for example, a small molecule compound surrounded by Phe60, Gln87, Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, Ser258, Cys259, Asp262, Cys263, Leu264, and His266, which are contained in the extracellular domain of human interleukin-17 receptor A (IL-17RA). The compound contains a compound having the effect of inhibiting the binding of interleukin-17A (IL-17A) to IL-17RA in humans, etc., or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which can bind to IL-17RA through non-covalent interactions, including van der Waals forces acting between at least 13 of these amino acid residues in the space defined by the compound, and preferably further including at least one type of intermolecular interaction selected from the group consisting of ionic bond, hydrogen bond, C-H-π interaction, and hydrophobic interaction acting between predetermined ones of the amino acid residues.

Description

[Technical Field]

[0001] This invention relates to a small molecule compound, an IL-17A activity inhibitor, that inhibits the binding of interleukin-17A (IL-17A) to interleukin-17 receptor A (IL-17RA). Furthermore, this invention relates to a pharmaceutical product containing such an IL-17A activity inhibitor as an active ingredient, for treating or preventing symptoms and diseases of intervertebral disc tissue, such as intervertebral disc degeneration, and inflammatory skin diseases, such as psoriasis. [Background technology]

[0002] Interleukin-17A (IL-17A) is a cytokine produced by T helper 17 (Th17) cells, a subset of T cells. IL-17A binds to the interleukin-17 receptor (IL-17R) found in various cells, regulating the expression of various genes by triggering JAK-STAT intracellular signaling. Abnormal IL-17 production and abnormalities in JAK-STAT intracellular signaling are deeply involved in tissue inflammation, autoimmune diseases, and tumor formation. Recently, it has also been reported that IL-17 levels increase in nucleus pulposus cells of degenerated or herniated intervertebral discs, along with IL-4, IL-6, IL-12, and IFN-γ (Non-patent documents 1 and 2).

[0003] IL-17A is a homodimeric protein (A and B chains). On the other hand, IL-17R is a protein composed of two subunits, interleukin-17 receptor A (IL-17RA) and interleukin-17 receptor C (IL-17RC), with IL-17RA further composed of two fibronectin type III domains (D1 and D2). The crystal structure of the complex of IL-17A and the extracellular domains of IL-17RA has been identified, and the two domains of IL-17RA contain three major binding sites (pockets) with IL-17A: Ans89~Glu92 and Asp121~Glu125 in the D1 domain, Ser257~Asp262 in the D2 domain, and the site formed by the helix linker Thr163~Ser167 that links the D1 and D2 domains.

[0004] Research and development of IL-17A activity inhibitors has primarily focused on biological agents whose main component is a so-called neutralizing antibody, such as anti-IL-17A antibodies that target IL-17A and inhibit its binding to IL-17RA, or conversely, anti-IL-17RA antibodies that target IL-17RA and inhibit its binding to IL-17A.

[0005] For example, Patent Document 1 (JP 2016-508508, Novartis AG) describes an antibody (anti-IL-17A antibody) that contains a CDR having a specific amino acid sequence, which specifically binds to homodimeric IL-17A and heterodimeric IL-17AF of humans, mice, etc., but does not specifically bind to homodimeric IL-17F, and which can inhibit or block the binding between IL-17A and its receptor by binding to IL-17A, and can reduce or neutralize IL-17A activity. Patent Document 1 further states that such an antibody can be used to treat autoimmune and inflammatory disorders, such as arthritis, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disease, systemic lupus erythematosus (SLE), lupus nephritis, asthma, multiple sclerosis, and cystic fibrosis.

[0006] Patent Document 2 (JP 2010-505416, Amgen Incorporated) describes an antibody (anti-IL-17RA antibody) that inhibits the binding of human or other IL-17A and / or IL-17F to human or other IL-17RA, comprising a CDR having a specific amino acid sequence, and a pharmaceutical composition for treating inflammation (e.g., arthritis), asthma, autoimmune diseases, etc., comprising the antibody. Patent Document 2 further describes a method for inhibiting the production of at least one cytokine, chemokine, matrix metalloproteinase, or other molecule (e.g., IL-6, IL-8, CXCL1, CXCL2, GM-CSF, G-CSF, M-CSF, IL-1β, TNFα, RANK-L, LIF, PGE2, IL-12, MMP3, MMP9, GROα, NO, and C-telopeptide) associated with IL-17RA activation, comprising administering the IL-17RA to a patient. Patent Document 3 (JP 2017-511316, Kirin-Amgen, Inc.) describes a method for treating psoriasis of the nail or scalp using an antibody (preferably containing a CDR having a specific amino acid sequence) that specifically binds to IL-17RA and has antagonist activity.

[0007] Furthermore, as psoriasis treatments containing antibodies as described in Patent Documents 1 to 3, a subcutaneous injection containing the anti-IL-17A antibody "secukinumab" (trade name "Cosentyx", Novartis Pharma) as the active ingredient, and a subcutaneous injection containing the anti-IL-17RA antibody "brodalumab" (trade name "Lumicef", Kyowa Hakko Kirin) as the active ingredient are already manufactured and sold in Japan.

[0008] On the other hand, Non-Patent Literature 3 discloses that the "pocket" of the extracellular domain of IL-17RA, namely the region composed of Asn89, Thr90, Asn91, Glu92, Asp121, Pro122, Asp123, Gln124, Glu125 in the D1 domain, Ser257, Ser258, Cys259, Leu260, Asn261, Asp262 in the D2 domain, and Thr163, Pro164, Cys165, Met166, Ser167 in the helix linker, was designated as the target site for a drug that inhibits binding to IL-17A, and that a cyanidin compound (A18) represented by the following formula was able to competitively inhibit the binding of IL-17A to IL-17RA by interacting with Asp121, Gln124, Ser168, and Asp262 in the aforementioned pocket. Furthermore, the study describes how the inhibitory activity of compound A18 is significantly reduced against mouse IL-17RA in which Asp262, which is maintained between human IL-17RA and mouse IL-17RA, is mutated (for example, substituted with Ala), suggesting that this amino acid residue is important for the binding of IL-17A to IL-17RA. In particular, it is noted that the hydrogen bond between the hydroxyl group (-OH) at the 3' position of the B ring and Gln124, the hydrogen bond between the hydroxyl group at the 3 position of the C ring and Asp262, and, to a slightly lesser extent, the hydrogen bond between the hydroxyl group at the 5 position of the C ring and Leu264 significantly influence the IL-17RA inhibitory activity described above. It is also noted that the IL-17RA inhibitory activity is almost completely eliminated in compounds in which the C ring is modified from a 6-membered ring to a 5-membered ring.

[0009] [ka]

[0010] Furthermore, Non-Patent Document 3 (Liu et al) discloses that compound A18 can be used to inhibit the expression of IL-17A-induced genes in human and mouse cells, suppress IL-17A-dependent skin hyperplasia in mice, suppress Th17 cell-dependent inflammation in mice, and alleviate airway inflammation in a mouse model of severe steroid-resistant asthma. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] Special Publication No. 2016-508508 [Patent Document 2] Special Publication No. 2010-505416 [Patent Document 3] Special Publication No. 2017-511316 [Non-patent literature]

[0012] [Non-Patent Document 1] Aggarwal, S. et al., The Journal of biological chemistry 278, 1910-1914 (2003) [Non-Patent Document 2] Park, H. et al., Nature immunology 6, 1133-1141 (2005) [Non-Patent Document 3] Liu et al., Sci Signal. 10(647), eaaf8823 (2017) [Overview of the Initiative] [Problems that the invention aims to solve]

[0013] Pharmaceuticals (biological preparations) containing antibodies (neutralizing antibodies) as active ingredients, as described in Patent Documents 1-3, are problematic due to the potential for serious side effects and their high cost. Therefore, if small molecule compounds that can overcome these problems can be used as IL-17 activity inhibitors, their value would be high.

[0014] On the other hand, Non-Patent Document 3 describes that a specific low-molecular-weight compound (cyanidin) can be used as an IL-17A activity inhibitor, but there was room for improvement in its IL-17A activity inhibitory ability.

[0015] In one aspect, the present invention aims to provide a small molecule compound (IL-17A activity inhibitor) that has superior IL-17A activity inhibitory ability compared to conventional compounds.

[0016] Furthermore, while a relationship between IL-17A and intervertebral disc degeneration has been suggested, the specific role that IL-17A plays in intervertebral disc degeneration remains unclear. In previous studies, intervertebral disc nucleus pulposus cells were cultured in an atmosphere with normal oxygen concentrations, which differs significantly from the hypoxic environment of actual intervertebral disc tissue in vivo. It was unclear what effect inhibiting IL-17A activity in intervertebral disc nucleus pulposus cells when cultured in a hypoxic environment that replicates the microenvironment of intervertebral disc tissue would have, particularly whether it could suppress the progression of intervertebral disc degeneration or the production of pain-causing substances.

[0017] Therefore, in another aspect, the present invention also aims to provide novel applications for the treatment or prevention of intervertebral disc degeneration of small molecule compounds having IL-17A activity inhibitory ability (IL-17A activity inhibitors) by clarifying the detailed mechanism of IL-17A involvement in intervertebral disc degeneration. [Means for solving the problem]

[0018] To discover candidate compounds that can inhibit IL-17A activity and solve the above problems, the inventors performed in silico analysis in the following three stages. First, using the crystal structure information (PDB ID: 4HSA) of the complex of IL-17A and its receptor (IL-17RA), they identified the region on IL-17RA that IL-17A interacts with (hereinafter referred to as the "interaction region"). Then, they determined the structural chemical conditions of a group of compounds that can bind to this region and block the binding of IL-17A using the software "DRFF" (Horio K, Muta H, Goto J, Hirayama N (2007) A simple method to improve the odds in finding 'lead-like' compounds from chemical libraries. Chem. Pharm. Bull., 55, 980-984). The interaction region revealed in this study is a space surrounded by 28 amino acid residues, which partially overlaps with the pocket composed of 20 amino acid residues mentioned in Non-Patent Document 3, but is a larger space. Secondly, we searched our in-house compound database, which consists of information on approximately 6 million commercially available compounds, for 5,500 compounds that best satisfied the structural chemical conditions obtained in the previous study. Thirdly, we precisely determined the interaction between the interaction region and the 5,500 compounds using the docking software "ASEDock" (Goto, J.; Kataoka, R.; Muta, H.; Hirayama, N. (2008) ASEDock-docking based on alpha spheres and excluded volumes. J. Chem. Inf. Model, 48, 583-590.), and selected candidate compounds for biological evaluation based on the interaction energy between the compound and IL-17RA (GBVI / WSA_dG. Corbeil, CR; Williams, CI; Labute, P. (2012) Variability in docking success rates due to dataset preparation. J. Comput.-Aided Mol. Des., 26, 775-786.).

[0019] On the other hand, the inventors of this invention were the first to discover that when nucleus pulposus cells (NP cells) collected from rat intervertebral discs were cultured under 1% hypoxic conditions, which approximate the growth environment of intervertebral discs in vivo, and IL-17A was added, the expression levels of several genes (factors) that promote inflammation and nucleus pulposus degeneration in intervertebral discs increased. Based on this, the inventors added candidate compounds along with IL-17A to nucleus pulposus cells cultured under the hypoxic conditions described above to test whether several compounds that showed high IL-17A activity inhibitory ability (low GBVI / WSA_dG, which is a negative value) in the above-mentioned in silico analysis actually possess IL-17A activity inhibitory ability in human or rat nucleus pulposus cells. As a result, they found that the expression levels of the aforementioned specific genes were suppressed by adding the candidate compounds according to the present invention. For example, the expression level of COX-2, which is said to be a pain-inducing factor, was significantly suppressed compared to the compound in Non-Patent Document 3, demonstrating that the candidate compounds according to the present invention have superior IL-17A activity inhibitory ability compared to the compound in Non-Patent Document 3.

[0020] Through such research, the inventors have revealed that candidate compounds in silico, which have been shown to interact with the amino acid residues constituting the interaction region identified above with a predetermined strength, possess the ability to inhibit IL-17A activity by competitively binding to IL-17RA, not only the compounds used in the examples of the present invention but also other compounds, and have thus completed the present invention.

[0021] The compounds disclosed in Non-Patent Document 3 were discovered through the following procedure. First, based on the substructure of IL-17A (ligand) that interacts with IL-17RA in the crystal structure, a site (pocket) on IL-17RA to which the inhibitor can bind was defined. Second, using the docking method, the molecule that most appropriately binds to this pocket was searched for from the NCI's compound library, which consists of approximately 90,000 compounds. In contrast, the approach of the present invention first identifies a region on IL-17RA that can interfere with the interaction with IL-17A, based on the three-dimensional structure of IL-17RA (receptor) alone. The region that can be identified by this method is significantly broader than the region identified in Non-Patent Document 3. Furthermore, this region also includes a region that does not participate in so-called receptor-ligand binding, but where the interaction between ligand and receptor is interfered with by the binding of a small molecule compound. In other words, compounds with completely different structures from the type of compounds that bind to the pocket identified in Non-Patent Document 3 can strongly bind to this region as inhibitors. The compounds of the present invention can be said to have been discovered as a result of searching for compounds with strong binding affinity to such interaction regions. Because the compounds of the present invention have a larger molecular size than the compounds in Non-Patent Document 3, it is presumed that they have superior IL-17A activity inhibitory ability by covering a wider portion of the interaction region and interacting more stably. For example, representative compounds of the present invention interact with amino acids of IL-17RA such as Cys154, Lys160, and Ser170, and particularly with amino acid residues that were not targeted in Non-Patent Document 3, such as Cys154, which has high commonality among the compounds of the present invention, through hydrogen bonding, CH-π interactions, etc. It is also thought that the compounds of the present invention exhibit superior inhibitory activity against IL-17A as described above by binding to IL-17RA in a way that interacts with such amino acid residues.

[0022] In other words, the entire present invention provides, for example, the following inventions. [Section 1] In the extracellular domain of human interleukin-17 receptor A (IL-17RA), within the space surrounded by Phe60, Gln87, Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, Ser258, Cys259, Asp262, Cys263, Leu264, and His266, non-covalent interactions, including van der Waals forces, act between at least 13 of these amino acid residues. An IL-17A activity inhibitor comprising a compound that inhibits the binding of interleukin-17A (IL-17A) to IL-17RA in human or non-human animals, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which can bind to IL-17RA, or can bind to IL-17RA by non-covalent interactions, including van der Waals forces, acting between at least 13 of the amino acid residues in a space surrounded by amino acid residues corresponding to the 28 amino acid residues contained in the extracellular domain of IL-17RA in non-human animals (provided that the homology of these amino acid residues is 80% or more). [Section 2] The IL-17A activity inhibitor according to item 1, wherein the non-covalent interaction involves at least one intermolecular interaction selected from the group consisting of ionic bonding, hydrogen bonding, CH-π interaction, cation-π interaction, and hydrophobic interaction, acting between the compound and at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Ser168, Ser170, Ser258, Asp262, Leu264, and His266. [Section 3] An IL-17A activity inhibitor as described in item 2, wherein the intermolecular interaction includes at least a hydrogen bond or CH-π interaction with Cys154. [Section 4] The IL-17A activity inhibitor according to item 2 or 3 may have at least one selected from the group consisting of a hydrogen bond with Asp121, a CH-π interaction and a hydrogen bond with Pro122, a CH-π interaction and a hydrogen bond with Asp123, an ionic bond, a hydrogen bond and a CH-π interaction with Lys160, and a CH-π interaction with Ser170.

[0023] [Item 5] ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​B may be replaced by (B1), and / or C 1-3 (B2) A divalent group derived from a carbamoyl group (amide bond) which may be linked to a divalent group derived from an alkyl-carbonyl group, (B3) A divalent group derived from a substituted 5-14 member aromatic heterocycle, (B4) A divalent group derived from a substituted 3-14 member non-aromatic heterocycle, (B4) A substituted C 3-10 Cycloalkyl groups, (B5) may be substituted C 3-10 (B6) represents a cycloalkenyl group, (B7) an optionally substituted 6-14 member aromatic hydrocarbon ring group (aryl group), (B8) an ester bond or thioester bond, or (B8) a keto group or thioketo group. L 2 is, (L 2 1) Single bond, (L 2 2) C 1-6 Alkylene group, or (L 2 3) C 1-3 Alkenylene group (carbon-carbon double bond is L) 2 It may be formed between adjacent carbon atoms of B or C. C is (C1) a divalent group (amide bond) derived from an N-substituted carbamoyl group, (C2) a divalent group derived from an N-substituted 5-14 member aromatic heterocycle, (C3) a divalent group derived from an N-substituted 3-14 member non-aromatic heterocycle, (C4) an N-substituted C 3-10 Cycloalkyl groups, (C5) may be substituted. 3-10 A cycloalkenyl group, a (C6) optionally substituted 6-14 member aromatic hydrocarbon ring group (aryl group), or a (C7) ester bond or thioester bond, L 3 is, (L 3 1) Single bond, (L 3 2) A divalent group derived from the carbamoyl group (amide bond) and / or a divalent group derived from the imino group, and / or substituted, C 1-3 Alkylene group, (L 3 3) C 1-3An ether bond or thioether bond may be linked to an alkenylene group, or (L 3 4) Represents a divalent group (amide bond) derived from a carbamoyl group, which may be linked to a divalent group derived from an amino group. D may be replaced by C (D1). 3-10 Cycloalkyl groups, (D2) may be substituted C 3-10 Cycloalkenyl group, (D3) optionally substituted 6-14 member aromatic hydrocarbon ring group (aryl group), (D4) optionally substituted 5-14 member aromatic heterocyclic group, (D5) optionally substituted 3-14 member non-aromatic heterocyclic group, or (D6) optionally substituted C 1-3 Represents an alkyl group. [Section 6] An IL-17A activity inhibitor as described in item 5, which further satisfies the requirements of any one of items 1 to 4. [Section 7] The compound (I) is a site where hydrogen bonding or CH-π interaction occurs with Cys154, The part A (A6) having a group that acts as a donor or acceptor for a hydrogen atom; The site B having a group that acts as a donor or acceptor for a hydrogen atom, which is site (B1) or (B3); The (C1), (C2), (C3), (C6), or (C7) portion C having a group that acts as a donor or acceptor for a hydrogen atom; The (L) has a group that acts as a donor or acceptor for a hydrogen atom (it may have such a group as a substituent). 1 2) or (L 1 4) Part L 1 ; The (L) has a group that acts as a donor or acceptor for a hydrogen atom (it may have such a group as a substituent). 2 2) Part L 2 ;or The portion C having π electrons, which is (C2) or (C6), An IL-17A activity inhibitor according to claim 5 or 6, having at least one of the following: [Section 8] The compound (I) has a site where hydrogen bonding occurs with Asp121, which is site A, which is site (A3), (A4), or (A6), or site (L 1 2) The aforementioned part L 1 An IL-17A activity inhibitor according to item 5 or 6, having at least one of the following: [Section 9] The IL-17A activity inhibitor according to claim 5 or 6, wherein the compound (I) has at least one site A which is (A4) or (A5), or site B which is (B3) or (B5), as a site where CH-π interaction or hydrogen bonding occurs with the Pro122. [Section 10] The IL-17A activity inhibitor according to claim 5 or 6, wherein the compound (I) has at least one site A, which is (A5), or site C, which is (C6) or (C8), as a site where CH-π interaction or hydrogen bonding occurs with Asp123. [Section 11] The IL-17A activity inhibitor according to claim 5 or 6, wherein the compound (I) has at least one site D which is (D1), (D3), or (D5) as a site where an ionic bond, hydrogen bond, or cation-π interaction occurs with the Lys160. [Section 12] The IL-17A activity inhibitor according to claim 5 or 6, wherein the compound (I) has at least one site D which is (D3) or (D5) as a site where a CH-π interaction occurs with the Ser170.

[0024] [Section 13] The IL-17A activity inhibitor according to any one of items 5 to 12, wherein the compound (I) is one of the compounds represented by the following structural formulas (1) to (36) (hereinafter referred to as "compounds (1) to (36)") or a derivative thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0025] [Section 14] The IL-17A activity inhibitor described in item 13, wherein compound (I) is compound (1) or a derivative of compound (1) modified from the original compound (1) to satisfy at least one condition selected from the group consisting of [X], [Y], and [Z] below: [X] Compared to compound (1), the sum of the van der Waals forces between Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, and Leu264 is enhanced; [Y] Compound (1) has a site where at least one of the CH-π interaction with Pro122, the hydrogen bond with Cys154, or the ionic bond with Lys160 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, and Leu264; [Z] Compared to compound (1), it has a site that reduces the exposure of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, and Leu264 to the solvent side. [Section 15] The IL-17A activity inhibitor described in item 13, wherein compound (I) is compound (2), or a derivative of compound (2), modified from the original compound (2) to satisfy at least one condition selected from the group consisting of [X], [Y], and [Z] below: [X] Compared to compound (2), the sum of the van der Waals forces between Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, Pro254, Phe256, Ser258, Cys259, Asp262, Leu264 and His266 is enhanced; [Y] Compound (2) has a site where at least one of the CH-π interaction with Asp123, the hydrogen bond with Cys154, or the CH-π interaction with Ser170 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, Pro254, Phe256, Ser258, Cys259, Asp262, Leu264, and His266; [Z] Compared to compound (2), it has a site that reduces the exposure to the solvent side of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, Pro254, Phe256, Ser258, Cys259, Asp262, Leu264, and His266. [Section 16] The IL-17A activity inhibitor described in item 13, wherein compound (I) is compound (5) or a derivative of compound (5) modified from the original compound (5) to satisfy at least one condition selected from the group consisting of [X], [Y], and [Z] below: [X] Compared to compound (5), the sum of the van der Waals forces between Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264, and His266 is enhanced; [Y] Compound (5) has a site where at least one hydrogen bond with Cys154 or Lys160 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264 and His266; [Z] Compared to compound (5), it has a site that reduces the exposure to the solvent side of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264, and His266. [Section 17] The IL-17A activity inhibitor described in item 13, wherein compound (I) is compound (9) or a derivative of compound (9) modified from the original compound (9) to satisfy at least one condition selected from the group consisting of [X], [Y], and [Z] below: [X] Compared to compound (9), the sum of the van der Waals forces between Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 is enhanced; [Y] The compound (9) has a site where at least one of the CH-π interaction with Asp121, the hydrogen bond with Cys154, or the CH-π interaction with Ser170 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266; [Z] Compared to compound (9), it has a site that reduces the exposure to the solvent side of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266. [Section 18] The IL-17A activity inhibitor described in item 13, wherein compound (I) is compound (11) or a derivative of compound (11) modified from the original compound (11) to satisfy at least one condition selected from the group consisting of [X], [Y], and [Z] below: [X] Compared to compound (11), the sum of van der Waals forces between Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 is enhanced; [Y] The compound (11) has a site where at least one CH-π interaction or hydrogen bond with Cys154 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266; [Z] Compared to compound (11), it has a site that reduces the exposure of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 to the solvent side.

[0026] [Section 19] An expression regulator containing an IL-17A activity inhibitor as described in any one of items 1 to 18, for regulating the expression level of genes whose expression level changes upon binding of IL-17A to IL-17RA in cells expressing IL-17RA. [Section 20] The gene expression regulator described in item 19 is a gene whose expression is upregulated by the binding of IL-17A to IL-17RA, and is intended to suppress its expression. [Section 21] The gene expression regulator according to claim 20, wherein the gene is at least one selected from the group consisting of IL-6, COX-2, mPGES1, MMP-3, MMP-13, and CXCL1. [Section 22] The gene expression regulator described in item 20 is a gene whose expression is enhanced by phosphorylation of p38, and is intended to suppress its expression. [Section 23] The expression regulator according to any one of claims 19 to 22, wherein the cells expressing IL-17RA are intervertebral disc nucleus pulposus cells. [Section 24] The expression regulator according to item 23, wherein the intervertebral disc nucleus pulposus cells are intervertebral disc nucleus pulposus cells cultured under hypoxic conditions, or intervertebral disc nucleus pulposus cells present in intervertebral disc tissue. [Section 25] The expression regulator according to any one of claims 19 to 24, wherein the cells expressing IL-17RA are keratinocytes or other epidermal cells.

[0027] [Section 26] A pharmaceutical product for the treatment or prevention of a disease in which the binding of IL-17A to IL-17RA is associated with symptoms, comprising as an active ingredient an IL-17A activity inhibitor as described in any one of items 1 to 18, or an expression regulator as described in any one of items 19 to 25. [Section 27] The medicine according to paragraph 26, wherein the disease associated with the binding of IL-17A to IL-17RA is lumbar or cervical disc disease, herniated disc, spondylolysis / spondylolisthesis, lumbar spinal stenosis, degenerative lumbar spondylolisthesis, or degenerative lumbar scoliosis. [Section 28] The medicine according to paragraph 26, wherein the disease for which the binding of IL-17A to IL-17RA is associated with symptoms is psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, or erythrodermic psoriasis.

[0028] [Section 29] The extracellular domains of human IL-17RA include Phe60, Gln87, Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, and Ser258. From the three-dimensional molecular model of the space enclosed by Cys259, Asp262, Cys263, Leu264, and His266, or the three-dimensional molecular model of the space enclosed by amino acid residues corresponding to the 28 amino acid residues contained in the extracellular domain of IL-17RA in non-human animals (provided that the homology of these amino acid residues is 80% or more), and the three-dimensional molecular model of the candidate compound, The binding stability between the candidate compound and IL-17RA is evaluated by non-covalent interactions, including van der Waals forces, that occur between at least 13 atoms or groups of atoms among the amino acid residues and atoms or groups of atoms in the candidate compound. A screening method for IL-17A activity inhibitors, comprising the step of estimating whether the candidate compound has the effect of inhibiting the binding of IL-17A to IL-17RA by competitively binding to IL-17RA with IL-17A. [Section 30] The screening method according to item 29, further comprising the step of comparing the binding stability of the candidate compound with the binding stability of the compounds (1) to (36).

[0029] [Section 31] A method for inhibiting the binding of IL-17A to IL-17RA, comprising the step of contacting IL-17RA with an IL-17A activity inhibitor described in any one of items 1 to 16 in vitro in humans and other animals. [Section 32] A method for regulating the expression of a gene whose expression level changes upon binding of IL-17A to IL-17RA, comprising the step of contacting a cell expressing IL-17RA with an expression regulator described in any one of items 17 to 22 in vitro in humans and other animals.

[0030] In other aspects, the present invention provides methods for treating and preventing a particular disease, comprising administering an effective amount of the compound of the present invention; the compound of the present invention used as an IL-17 activity inhibitor administered as an active ingredient; the use of the compound of the present invention as an IL-17 activity inhibitor; the use of the compound of the present invention in the manufacture of a pharmaceutical for the treatment or prevention of a particular disease; and other inventions derived from the uses of the compound of the present invention. [Effects of the Invention]

[0031] The low-molecular-weight compounds provided by the present invention exhibit superior IL-17A activity inhibitory ability compared to conventional low-molecular-weight compounds, and are expected to be usable as active ingredients in pharmaceuticals for the treatment or prevention of conditions such as intervertebral disc degeneration and psoriasis, as well as for pain relief. [Brief explanation of the drawing]

[0032] [Figure 1]Figure 1 shows the molecular structure as drawn by software in in silico analysis. [A] Molecular structure representing the complex of human IL-17A and human IL-17RA. [B] Molecular structure representing human IL-17RA. The cluster of small spheres visible in the central "groove" is a group of pseudoatoms representing the expected positions of atoms in a candidate compound for human IL-17A activity inhibition when that compound is bound to human IL-17RA. It is estimated that amino acid residues within 3.5 Å of these pseudoatoms are subject to non-covalent interactions, including van der Waals forces, with the candidate compound. [C] Molecular structure showing a partial magnification of the "groove" of human IL-17RA and the group of pseudoatoms within it. When displayed in color, hydrophilic pseudoatoms are red and hydrophobic pseudoatoms are white. [D] Molecular structure showing compound (1) of the present invention bound to the "groove" of human IL-17RA, as an example of a candidate compound. When displayed in color, carbon atoms, oxygen atoms, nitrogen atoms, and hydrogen atoms are green, red, blue, and white, respectively. [Figure 2] Figure 2 is a schematic diagram illustrating the mode of non-covalent interaction between compound (1) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. The curved dotted lines around the molecule represent the binding surface between the compound of the present invention and human IL-17RA (specific amino acid residues in the interaction region). The straight dotted lines represent intermolecular interactions such as hydrogen bonds and CH-π interactions. The cloud surrounding the atoms of the compound of the present invention represents the exposure of the molecular surface to the solvent side; a larger cloud indicates greater exposure. Amino acid residues with thick circular outlines represent acidic or basic residues. The disk-shaped shadows around the circles indicate the degree of solvent exposure of the amino acid residue in the absence of the compound of the present invention, meaning that the binding of the compound reduces this solvent exposure. (The same applies to the diagrams relating to other compounds of the present invention below.) [Figure 3] Figure 3 is a schematic diagram illustrating the mode of non-covalent interaction between compound (2) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 4]Figure 4 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (4) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 5] Figure 5 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (5) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 6] Figure 6 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (6) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 7] Figure 7 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (7) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 8] Figure 8 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (8) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 9] Figure 9 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (9) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 10] Figure 10 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (10) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 11] Figure 11 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (11) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 12] Figure 12 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (12) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 13] Figure 13 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (13) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 14]Figure 14 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (14) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 15] Figure 15 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (15) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 16] Figure 16 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (16) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 17] Figure 17 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (17) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 18] Figure 18 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (18) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 19] Figure 19 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (19) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 20] Figure 20 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (20) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 21] Figure 21 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (21) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 22] Figure 22 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (22) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 23] Figure 23 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (23) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 24]Figure 24 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (24) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 25] Figure 25 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (25) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 26] Figure 26 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (26) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 27] Figure 27 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (27) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 28] Figure 28 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (28) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 29] Figure 29 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (29) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 30] Figure 30 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (30) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 31] Figure 31 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (31) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 32] Figure 32 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (32) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 33] Figure 33 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (33) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 34]Figure 34 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (34) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 35] Figure 35 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (35) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 36] Figure 36 is a schematic diagram illustrating the mode of non-covalent interaction between the compound (36) of the present invention and amino acid residues contained in the extracellular domain of human IL-17RA. [Figure 37] Figure 37 shows the results for [Reference Example 1]. [A] and [B] are histological immunohistochemical staining images of IL-17A in degenerated and normal human intervertebral disc tissue, respectively. Scale bar: 10 μm. [C] is a graph showing the percentage of IL-17A-positive cells in degenerated and normal intervertebral disc tissue. n=3. *: p<0.05. [Figure 38] Figure 38 shows the results for [Reference Example 2]. [A] Graphs showing the mRNA expression levels of IL-6, COX-2, mPGES1 (prostaglandin E synthase 1), MMP-3, and MMP-13 genes after 24 hours of culture under 1% oxygen conditions in rat NP cells administered with recombinant mouse IL-17A at concentrations of 20 or 50 ng / ml, and in the untreated group. *p<0.05, n=5. [B] Electrophoresis (left) and graph (right) showing the protein expression levels of COX-2 and IL-6, as well as β-actin as an internal control, after 24 hours of culture under 1% oxygen conditions in rat NP cells administered with IL-17A at a concentration of 50 ng / ml. *p<0.05, n=3. [C] Graph showing the transcriptional activity of COX-2 after administering IL-17A at a concentration of 50 ng / ml to rat NP cells and culturing them for 24 hours under 1% oxygen conditions (evaluated by promoter assay). *p<0.05, n=3. [Figure 39]Figure 39 shows the results for [Reference Example 3]. [A] Graphs showing the mRNA expression levels of IL-6, COX-2, mPGES1, MMP-3, and MMP-13 genes after 24 hours of culture under 1% oxygen conditions for each group: rat NP cells administered recombinant mouse IL-17A at a concentration of 50 ng / ml alone (IL-17A monotherapy group: "IL-17A" is "+", "anti-IL-17A" is "-"), and rat NP cells administered a mixed solution of IL-17A at a concentration of 50 ng / ml and anti-IL-17A antibody at a concentration of 0.5 μg / ml (anti-IL-17A neutralizing antibody combination therapy group: both "IL-17A" and "anti-IL-17A" are "+"). *p<0.05, n=3. [B] Electrophoretic graph showing the protein expression levels of COX-2, IL-6, and β-actin as an internal control after 24 hours of culture under 1% oxygen conditions for each of the IL-17A monotherapy group and the IL-17A monotherapy group. *p<0.05, n=3. [C] Graph corresponding to [B] above. [D] Graph showing the transcriptional activity of COX-2 after 24 hours of culture under 1% oxygen conditions for each of the rat NP cells: the group not administered either IL-17A or anti-IL-17A antibody (no-treatment group: both "IL-17A" and "anti-IL-17A" are "-"), the IL-17A monotherapy group, and the IL-17A monotherapy group (evaluated by promoter assay). *p<0.05, n=3. [Figure 40]Figure 40 shows the results for [Reference Example 4]. [A] Graph showing the mRNA expression levels of the COX-2, IL-17A, MMP-3, and MMP-13 genes after 24 hours of culture under 1% oxygen conditions in rat NP cells administered with 50 ng / ml of IL-6 and in the untreated group. *p<0.05, n=3. [B] Electrophoresis (left) and graph (right) showing the protein expression levels of COX-2 and β-actin as an internal control after 24 hours of culture under 1% oxygen conditions in rat NP cells administered with 50 ng / ml of IL-6. *p<0.05, n=3. [C] Graph showing the transcriptional activity of COX-2 after 24 hours of culture under 1% oxygen conditions in rat NP cells administered with 50 ng / ml of IL-6 (evaluated by promoter assay). *p<0.05, n=3. [Figure 41] Figure 41 shows the results for [Example 1]. [A] Graphs showing the mRNA expression levels of IL-6, COX-2, mPGES1, MMP-3, and MMP-13 genes after 24 hours of culture under 1% oxygen conditions for each group of rat NP cells: the group administered recombinant mouse IL-17A alone at a concentration of 50 ng / ml (IL-17 group), and the groups administered recombinant mouse IL-17A at a concentration of 50 ng / ml and one of compounds (3), (2), (5), or (11) at a concentration of 50 μg / ml (IL17+STK group, IL17+PB group, IL17+Z9215 group, and IL17+P2000 group, respectively). *p<0.05, n=3. [B] Electrophoretic graph (left) and graph (right) showing the expression levels of COX-2 and IL-6 proteins after 24 hours of culture under 1% oxygen conditions for the IL-17 group and the IL-17+STK group, respectively. *p<0.05, n=3. [C] Graph showing the transcriptional activity of COX-2 after 24 hours of culture under 1% oxygen conditions for the rat NP cells in the group that was not administered either IL-17A or compound (1) (no-administration group: both "IL-17A" and "STK" are "-"), the IL-17 group, and the IL-17+STK group, respectively (evaluated by promoter assay). *p<0.05, n=3. [Figure 42]Figure 42 shows the results for [Example 2]. [A] Graph showing the mRNA expression level of IL-6 in human NP cells (normalized by β-actin). *p<0.05, n=3. [B] Graph showing the mRNA expression level of COX-2 (normalized by β-actin). *p<0.05, n=3. [Figure 43] Figure 43 shows the results for [Example 3]. [A] A graph showing the expression level of COX-2 mRNA after 24 hours of culture under 1% oxygen conditions for rat NP cells in groups treated with recombinant mouse IL-17A at a concentration of 50 ng / ml ("IL-17"+ / "Inhibitor"-), groups treated with IL-17A at a concentration of 50 ng / ml and 10 μM of p38 phosphorylation inhibitor SB203580, JNK phosphorylation inhibitor SP600125, or ERK phosphorylation inhibitor PD98059 ("IL-17"+ / "Inhibitor" SB, SP, or PD, respectively), and a control group ("IL-17"- / "Inhibitor"-). *p<0.05, n=3. [B] A graph showing the expression level of IL-6 mRNA for the same groups as in [A] above. *p<0.05, n=3. [C] Electrophoresis plot showing the protein expression levels of phosphorylated p38 (pp38), p38, phosphorylated JNK (pJNK), JNK, phosphorylated ERK (pERK), and ERK after 15 minutes of culture under 1% oxygen conditions for rat NP cells in groups administered 50 ng / ml of IL-17A ("IL-17"+ / "STK"-), groups administered 50 ng / ml of IL-17A and 50 μg / ml of compound (1) of the present invention ("IL-17"+ / "STK"+), and an untreated group ("IL-17"- / "STK"-). [D] Electrophoresis plot showing the protein expression levels of each protein after 30 minutes of culture under 1% oxygen conditions for the same groups as in [C] above. [E] Graph corresponding to the electrophoresis plot in [C] above. *p<0.05, n=4. [F] Graph corresponding to the electrophoresis plot in [D] above. *p<0.05, n=4. [Figure 44]Figure 44 shows the results for [Comparative Example 1]. [A] A graph showing the expression level of COX-2 mRNA in rat NP cells cultured for 24 hours under 1% oxygen conditions for two groups: the IL-17 group (50 ng / ml concentration of recombinant mouse IL-17A alone) and the cynd50μg / ml group (50 ng / ml concentration of IL-17A and 50μg / ml concentration of the compound from Non-Patent Document 3). n=3. [B] A graph comparing the expression level of COX-2 mRNA in the cynd50μg / ml group from [A] with the expression level of COX-2 mRNA in the IL-17+STK group obtained in [Example 1] (the latter is the relative value when the former is set to 1). *p<0.05, n=3. [Figure 45] Figure 45 is a schematic diagram illustrating the reaction pathways involving the interleukin 17 family (A, B, C, D, E, F). [Figure 46-1] Figure 46 shows the results of comparing parts of the amino acid sequences of human and rat IL-17RA using BLAST (https: / / blast.ncbi.nlm.nih.gov / Blast.cgi). Single underlines represent 28 predetermined amino acid residues in the interaction region, and double underlines represent amino acid residues that engage in non-covalent interactions (intermolecular interactions) other than van der Waals forces with representative compounds of the present invention (any of compounds (1) to (36)). The amino acid residue numbers displayed to the left and right of the sequences in this figure are the same as the amino acid residue numbers in Sequence IDs 1 and 2. For example, Cys154, which is included in the predetermined amino acid residues of the interaction region, corresponds to the 185th amino acid residue, C, in this figure. [Figure 46-2]Figure 46-2 shows the results of comparing parts of the amino acid sequences of human and mouse IL-17RA using BLAST (https: / / blast.ncbi.nlm.nih.gov / Blast.cgi). Single underlines represent 28 predetermined amino acid residues in the interaction region, and double underlines represent amino acid residues that engage in non-covalent interactions (intermolecular interactions) other than van der Waals forces with representative compounds of the present invention (any of compounds (1) to (36)). The amino acid residue numbers displayed to the left and right of the sequences in this figure are the same as the amino acid residue numbers in Sequence IDs 1 and 2. For example, Cys154, which is included in the predetermined amino acid residues of the interaction region, corresponds to the 185th amino acid residue, C, in this figure. [Figure 47] Figure 47 shows the results for [Example 4]. [A] Light microscope image of HE-stained mouse skin specimen. [B] Graph showing the thickness of the epidermal layer based on the light microscope image. Normal: normal group, IMQ: IMQ group (mice that developed psoriasis-like dermatitis due to imiquimod cream), DMSO: Sham group (mice that had DMSO applied to the affected area), STK: STK group (mice that had a DMSO solution of compound (3) applied to the affected area). [Figure 48] Figure 48 shows the results for [Example 4]. [A] Fluorescence micrograph of a fluorescent immunostained specimen of mouse skin using an anti-CXCL1 antibody. [B] Graph showing the CXCL1 expression area based on the fluorescence micrograph. Normal: normal group, IMQ: IMQ group (mice that developed psoriasis-like dermatitis with imiquimod cream), DMSO: Sham group (mice that had DMSO applied to the affected area), STK: STK group (mice that had a DMSO solution of compound (3) applied to the affected area). [Figure 49]Figure 49 shows the results for [Example 5]. [A] Light microscope image of an immunostained specimen of rat caudal vertebrae using anti-IL-6 antibody. [B] Graph showing the IL-6 positive cell expression rate based on the light microscope image. Normal: normal group, deg: degenerated group (rats with intervertebral disc degeneration); STK: STK group (mice injected with a DMSO solution of compound (3) after intervertebral disc degeneration); sham: Sham group (mice injected with DMSO after intervertebral disc degeneration). [Modes for carrying out the invention]

[0033] This invention encompasses inventions belonging to different categories (agents, pharmaceuticals, methods, etc.) in multiple aspects. Unless otherwise specified, matters described herein can be shared among different inventions in context.

[0034] In this specification, each substituent is defined as follows, unless otherwise specified.

[0035] "C 1-3 "Alkyl groups" refer to linear or branched saturated hydrocarbon groups having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and isopropyl.

[0036] "C 4-6 "Alkyl groups" refer to linear or branched saturated hydrocarbon groups with 4 to 6 carbon atoms. Examples include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0037] "C 3-10 A "cycloalkyl group" refers to a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0038] "C3-10 A "cycloalkenyl group" refers to a cyclic unsaturated hydrocarbon group having 3 to 10 carbon atoms and one carbon-carbon double bond. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0039] A "6-14 member aromatic hydrocarbon ring group (aryl group)" refers to a group derived from an aromatic cyclic compound with 6 to 14 members (preferably 6 to 10 members) in which carbon atoms are ring constituent atoms. Examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

[0040] A "5-14 member aromatic heterocycle" refers to an aromatic cyclic compound with 5 to 14 members (preferably 5 to 10 members) that contains at least one (preferably 1 to 4) heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen atoms, in addition to carbon atoms, as ring constituent atoms. Examples include the following: Five or six-membered monocyclic aromatic heterocyclic compounds such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, phlopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, phlopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazo Pyrimidines, pyrazolopyrimidines, pyrazolotriazines, naphtho[2,3-b]thiophene, phenoxatiin, indole, isoindole, 1H-indazole, purines, isoquinolines, quinolines, phthalazines, naphthyridines, quinoxalines, quinazolines, cinnolines, carbazoles, β-carbolins, phenanthridines, acridines, phenazines, phenothiazines, phenoxazines, and phenoxazines are examples of 8-14 membered condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocycles.

[0041] A "3-14 member non-aromatic heterocycle" refers to a non-aromatic cyclic compound with 3 to 14 members (preferably 4 to 10 members) that contains at least one (preferably 1 to 4) heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen atoms, in addition to carbon atoms, as ring constituent atoms. Examples include the following: Aziridine, oxirane, thiran, azetidine, oxetane, thietan, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydroxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothioran, morpholine, thiomorpholine, azepanin, diazepan, azepine, azocan, diazocan, oxepan, and other 3-8 membered monocyclic non-aromatic heterocyclic compounds; Dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoazepine, tetrahydroquinoxaline, tetrahydrophenanthidine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carbolin, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline, and other 9-14 membered condensed polycyclic (preferably 2 or 3 cyclic) non-aromatic heterocycles.

[0042] "C that can be replaced 3-10 Cycloalkyl group, "C may be substituted" 3-10 Cycloalkenyl group, optionally substituted 6-14 member aromatic hydrocarbon ring group (aryl group), optionally substituted 5-14 member aromatic heterocyclic group, optionally substituted 3-14 member non-aromatic heterocyclic group, optionally substituted C 1-3 "Alkyl alkyl group", "C which may be substituted" 4-6 Examples of substituents that alkyl groups may have include those listed in "Substituent Group A" below: [Substituent group A] (1) Halogen atom; (2) Nitro group; (3) Cyano group; (4) Oxo group; (5) Hydroxyl group; (6) C may be halogenated 1-6 Alkoxy group; (7)C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy); (8)C 7-16 Aralkyloxy group (e.g., benzyloxy); (9) 5-14 member aromatic heterocyclic oxy groups (e.g., pyridyloxy); (10) 3-14 member non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy, piperidinyloxy); (11)C 1-6 Alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), C 1-6 Alkyl-thiocarbonyloxy groups (e.g., thioacetoxy, thiopropanoyloxy); (12)C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (13)C 1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy); (14) Mono- or di-C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15)C 6-14 Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5-14 member aromatic heterocyclic carbonyloxy group (e.g., nicotinoyloxy); (17) 3-14 member non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinyl carbonyloxy, piperidinyl carbonyloxy); (18) C which may be halogenated 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy); (19)C 1-6 C may be substituted with an alkyl group. 6-14 Aryl sulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy); (20) C may be halogenated 1-6 Alkylthio group; (21) A substituted 5- to 14-membered aromatic heterocyclic group; (22) A 3- to 14-membered non-aromatic heterocyclic group which may be substituted; (23) Formyl group; (24) Carboxylic group, thiocarboxyl group; (25) C may be halogenated 1-6 Alkyl-carbonyl group; (26)C 6-14 Aryl-carbonyl group; (27) 5-14 member aromatic heterocyclic carbonyl group; (28) 3-14 member non-aromatic heterocyclic carbonyl group; (29)C 1-6 Alkoxy-carbonyl group; (30)C 6-14 Aryloxycarbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (31)C 7-16 Aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (32) Carbamoyl group; (33) Thiocarbamoyl group; (34) Mono- or di-C 1-6 Alkyl-carbamoyl group; (35)C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl); (36) 5-14 member aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl); (37) 3-14 member non-aromatic heterocyclic carbamoyl group (e.g., morpholinyl carbamoyl, piperidinyl carbamoyl); (38) C may be halogenated 1-6 Alkyl sulfonyl group; (39)C 6-14 Aryl sulfonyl group; (40) 5-14 member aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl); (41) C which may be halogenated 1-6 Alkyl sulfinyl group; (42)C 6-14Aryl sulfinyl groups (e.g., phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl); (43) 5-14 member aromatic heterocyclic sulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl); (44) Amino group, imino group; (45) Mono- or di-C 1-6 Alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 Arylamino group (e.g., phenylamino); (47) 5-14 member aromatic heterocyclic amino group (e.g., pyridylamino); (48)C 7-16 Aralkylamino group (e.g., benzylamino); (49) Formylamino group; (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino); (51)(C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino); (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 Alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino); (54)C 7-16 Aralkyloxycarbonylamino group (e.g., benzyloxycarbonylamino); (55)C 1-6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino); (56)C 1-6C which may be substituted with an alkyl group 6-14 an arylsulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino); (57)C which may be halogenated 1-6 an alkyl group; (58)C 2-6 an alkenyl group; (59)C 2-6 an alkynyl group; (60)C 3-10 a cycloalkyl group; (61)C 3-10 a cycloalkenyl group; (62)C 6-14 an aryl group.

[0043] The "divalent group (amide bond) derived from a carbamoyl group" may be in the direction of -NH-CO- or -CO-NH-.

[0044] The "divalent group (amide bond) derived from a carbamoyl group, which may be N-substituted and / or may be linked to a divalent group derived from a C 1-6 alkyl-carbonyl group" means that in the amide bond (-NH-CO- or -CO-NH-) as described above, the nitrogen atom (N) may have a substituent, or a divalent group derived from a C 1-6 alkyl-carbonyl group may be linked to one or both ends (preferably one end) of the amide bond, or both of these characteristics may be present. N-substitution includes the case where the two bonds of N form a ring structure (e.g., piperazine).

[0045] Examples of the substituent that the nitrogen atom of the amide bond has include those selected from the above-mentioned substituent group A.

[0046] The "divalent group derived from a C 1-3 alkyl-carbonyl group" is a divalent group (-C n [[ID=​-; n = 1 to 3) and a carbonyl group (-CO-) linked group, -C n H 2n -CO- may be in the orientation, -CO-C n H 2n - may be in the orientation.

[0047] “C 1-3 alkylene group” refers to a divalent group derived from a linear or branched saturated hydrocarbon (C 1-3 alkyl group) having 1 to 3 carbon atoms, for example, -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, -CH(CH3)-CH2-. “C 1-6 alkylene group” refers to a divalent group derived from a linear or branched hydrocarbon (C 1-6 alkyl group) having 1 to 6 carbon atoms. In addition to the above “C 1-3 alkylene group”, for example, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH(CH(CH3)2)), -CH(C2H4(CH3)2)-, -CH(C3H6(CH3)2)-, -CH(C(CH3)3)-, -CH(CH(CH3)2))-CH- are included.

[0048] “C 1-3 alkenylene group” refers to a divalent group derived from a linear or branched unsaturated hydrocarbon (C 1-3 alkenyl group) having 1 to 3 carbon atoms and having one carbon-carbon double bond, for example, -CH2=CH2-, -CH2=CH2-CH2-, -CH2-CH2=CH2-. However, when the carbon-carbon double bond is formed between the terminal carbon atom of the C 1-3 alkenyl group and the adjacent carbon atom (for example, in the compound of the present invention, the terminal carbon atom of the “C 1-3 alkenylene group” corresponding to site L2 and the carbon atom of site B adjacent thereto), for example, =CH2-, =CH2-CH2-, =CH2-CH2-CH2, etc. are also included in the “C<http: / / www.wipo.int / standards / XMLSchema / ST36 / XMLSchema / ST36-20020311 / XMLSchema / ST36-20020311- 1-3 alkenylene group”. The cis and trans positions due to the unsaturated bond may be either.

[0049] "C may be linked to a divalent group (amide bond) derived from the carbamoyl group." 1-3 The alkylene group is the C mentioned above. 1-3 This means that a divalent group (amide bond) derived from the carbamoyl group may be linked to one or both ends (preferably one end) of the alkylene group in either an -NH-CO- or -CO-NH- orientation. 1-3 Examples of alkylene groups include -(CH2) n -NH-CO-, -(CH2) n -CO-NH-, -NH-CO-(CH2) n -,-CO-NH-(CH2) n -(where n is an integer between 1 and 3) are examples.

[0050] —IL-17 activity inhibitors— In one aspect of the present invention, the "IL-17 activity inhibitor" provided is a component of the extracellular domain of human interleukin-17 receptor A (IL-17RA), specifically Phe60, Gln87, Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, Ser258, Cys259, Asp262, Cys263, Leu264, and His26 The present invention contains a compound (first embodiment of the compound of the present invention) that inhibits the binding of IL-17A to interleukin 17A (IL-17A) by binding to IL-17RA competitively with interleukin 17A (IL-17A) through van der Waals forces or other non-covalent interactions acting between some of the 28 amino acid residues (these 28 amino acid residues may be collectively referred to herein as "a predetermined amino acid residue constituting the interaction region") in the space (interaction region) surrounded by these 6 amino acid residues, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0051] The "IL-17 activity inhibitors" described above inhibit the activation of IL-17RA, which is caused by the binding of IL-17A to IL-17RA. Therefore, it is possible to rephrase this as "IL-17RA activation inhibitors" (meaning that "IL-17 activity inhibitors" in this specification should be read as "IL-17RA activation inhibitors").

[0052] The amino acid sequence of human IL-17RA is shown in Sequence ID No. 1 (GenBank: AAH11624.1, https: / / www.ncbi.nlm.nih.gov / protein / AAH11624.1). In this specification, the first amino acid residue of the extracellular domain of human IL-17RA corresponds to the 32nd amino acid residue (Ser) of Sequence ID No. 1. Therefore, among the predetermined amino acid residues constituting the interaction region, for example, Phe60 (phenylalanine, the 60th amino acid residue of the extracellular domain), Cys154 (cysteine, the 154th amino acid residue of the extracellular domain), and His266 (histidine, the 266th amino acid residue of the extracellular domain) correspond to the 91st amino acid residue (Phe), the 185th amino acid residue (Cys), and the 297th amino acid residue (His) of Sequence ID No. 1, respectively. If necessary, the amino acid residue numbers in the “extracellular domain” as described above in this specification (and drawings) may be replaced with the amino acid residue numbers in SEQ ID NO: 1 (including the signal peptide, extracellular domain, transmembrane region (α-helix), and cytoplasmic domain of IL-17RA). It is obvious that the invention defined by the amino acid residues with the replaced numbers is substantially no different from the invention defined by the amino acid residues with the original numbers.

[0053] For comparison, the amino acid sequence of rat IL-17RA is shown in Sequence ID No. 2 (NCBI Reference Sequence: NP_001101353.2, https: / / www.ncbi.nlm.nih.gov / protein / NP_001101353.2). Figure 46-1 shows the results of comparing the portion of the IL-17RA amino acid sequence containing the predetermined amino acid residues that constitute the interaction region between human and rat. There is high homology between human and rat IL-17RA in the interaction region containing the predetermined amino acid residues (23 out of 28 predetermined amino acid residues are identical, and the sequence homology is 82.1%). Therefore, those skilled in the art will understand, not only from the results using human cells (against human IL-17RA) shown in Example 2 of this specification, but also from the results using rat cells (against rat IL-17RA) shown in Examples 1 and 3, and from the results of the in vivo test using rats shown in Example 5, that the compound of the present invention has an inhibitory effect on the activity of human IL-17RA and an effect on the expression of a certain gene, and furthermore, that it has an effect on preventing or treating a certain disease in humans.

[0054] For comparison, the amino acid sequence of mouse IL-17RA is shown in Sequence ID No. 3 (NCBI Reference Sequence: NP_032385.1, https: / / www.ncbi.nlm.nih.gov / protein / NP_032385.1). Figure 46-2 shows the results of comparing the portion of the IL-17RA amino acid sequence containing predetermined amino acid residues that constitute the interaction region between human and mouse. There is a high degree of homology between human and rat IL-17RA in the interaction region containing the predetermined amino acid residues (25 out of 28 predetermined amino acid residues are identical, and the sequence homology is 89.3%). Therefore, those skilled in the art can understand, not only from the results using human cells (against human IL-17RA) shown in Example 2 of this specification, but also from the results of the in vivo test using mice shown in Example 4, that the compound of the present invention has an inhibitory effect on the activity of human IL-17RA and an effect on the expression of predetermined genes, and furthermore, that it has an effect on preventing or treating predetermined diseases in humans.

[0055] In one aspect of the present invention, the IL-17A activity inhibitors of the present invention are defined by van der Waals forces and other non-covalent interactions between predetermined amino acid residues contained in the extracellular domain (interaction region) of human IL-17RA. Those skilled in the art will understand that even when such IL-17A activity inhibitors are used against non-human animals, preferably non-human animal IL-17RA, similar activity inhibitory activity will be achieved even when used against IL-17RA with sequence homology of 50% or more, 60% or more, preferably extracellular domain sequence homology, and particularly preferably interaction region (28 predetermined amino acid residues) sequence homology, or 95% or more. That is, the IL-17A activity inhibitors of the present invention are typically human IL-17A activity inhibitors, but are not limited thereto, and also encompass activity inhibitors of IL-17A from non-human mammals (preferably those having the sequence homology described above).

[0056] Conversely, in one aspect of the present invention, the IL-17A activity inhibitor of the present invention is defined by van der Waals forces and other non-covalent interactions between predetermined amino acid residues contained in the extracellular domain (interaction region) of IL-17RA in non-human animals. Those skilled in the art will understand that even when such an IL-17A activity inhibitor is used against IL-17RA in humans or other animals (preferably non-human mammals), similar activity inhibitory activity will be achieved even when used against IL-17RA with sequence homology of, for example, 50% or more, 60% or more, 70% or more, 75% or more, particularly preferably 80% or more, 85% or more, 90% or more, or 95% or more, including sequence homology of the entire length of IL-17RA, preferably the extracellular domain, and especially preferably the interaction region (28 predetermined amino acid residues). The sequence homology referred to herein can be calculated using general methods (tools), such as BLAST (Basic Local Alignment Search Tool).

[0057] The compound of the present invention binds to the interaction region by van der Waals forces acting between at least 13, preferably 14 or more, 15 or more, 16 or more, 17 or more, or 18 or more amino acid residues among the predetermined (28) amino acid residues that constitute the interaction region.

[0058] In one embodiment of the present invention, the compound of the present invention binds to the interaction region by van der Waals forces acting between at least 13, preferably 14 or more, 15 or more, 16 or more, 17 or more, or 18 or more amino acid residues out of 19 amino acid residues, specifically Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264, and His266, which are among the predetermined (28) amino acid residues constituting the interaction region.

[0059] In this invention, "van der Waals forces are at work" means that within the interaction region, at least one atom of the compound of the present invention and at least one atom of the amino acid residue are located within a distance of 3.5 Å or less. When such a result is obtained using a molecular structure simulator used in in silico analysis (e.g., the software "ASEDock"), it can be considered that "van der Waals forces are at work". Those skilled in the art can estimate van der Waals forces and other non-covalent interactions occurring between the target compound and the amino acid residue of IL-17RA (within the interaction region) by using "ASEDock" or other software (in silico analysis means) under appropriate conditions.

[0060] The compounds of the present invention are further preferably subjected to non-covalent interactions other than van der Waals forces (sometimes simply referred to as "intermolecular interactions" herein) with at least one of the predetermined amino acid residues constituting the interaction region. Examples of such intermolecular interactions include ionic bonds, hydrogen bonds, hydrophobic interactions, OH-π interactions, cation-π interactions, CH-π interactions (which are also hydrophobic interactions), and π-π interactions (which are also hydrophobic interactions). The number of amino acid residues with which intermolecular interactions occur is preferably two or more, more preferably three or more. The intermolecular interactions may be of any one type or two or more types.

[0061] Those skilled in the art can understand, by considering the disclosure herein along with common technical knowledge or known facts, what basic atomic, atomic group, and other molecular structures the compounds of the present invention and the predetermined amino acid residues constituting the interaction regions must have in order for each of the above-mentioned intermolecular interactions to function, and can appropriately utilize in silico analysis in this process. Furthermore, those skilled in the art can select compounds that can be used in the present invention by excluding compounds that do not possess the desired level of IL-17A inhibitory activity from among compounds having molecular structures designed based on such basic principles, without requiring excessive trial and error.

[0062] In one embodiment of the present invention, the compound of the present invention is subject to at least one intermolecular interaction (a non-covalent interaction other than van der Waals forces) selected from the group consisting of ionic bonds, hydrogen bonds, CH-π interactions, cation-π interactions, and hydrophobic interactions, between it and a predetermined amino acid residue constituting the interaction region, preferably at least one amino acid selected from the group consisting of Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Ser168, Ser170, Ser258, Asp262, Leu264, and His266. More preferably, the compounds of the present invention are subject to at least one intermolecular interaction (a non-covalent interaction other than van der Waals forces) selected from the group consisting of ionic bonds, hydrogen bonds, CH-π interactions, and hydrophobic interactions, with at least one amino acid selected from the group consisting of Pro122, Cys154, Lys160, Ser170, and Leu264.

[0063] In such embodiments, if the compound of the present invention engages in the above-mentioned predetermined intermolecular interaction with at least one amino acid residue selected from the group consisting of Asp121, Gln124, Ser168, and Asp262, which is targeted by the compound described in Non-Patent Document 3, it is preferable that the compound of the present invention further engages in the above-mentioned predetermined intermolecular interaction with other predetermined amino acid residues constituting the interaction region, namely at least one amino acid selected from the group consisting of Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Ser170, Ser258, Leu264, and His266.

[0064] In another aspect of the present invention, the "IL-17 activity inhibitors" provided include a compound represented by general formula (I) (compound (I), a second embodiment of the compound of the present invention), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0065] [ka]

[0066] The details of each symbol in general formula (I) are as follows: A may be replaced by C (A1). 3-10 Cycloalkyl groups, (A2) may be substituted C 3-10 (A3) A cycloalkenyl group, (A4) A substituted 6-14 member aromatic hydrocarbon ring group (aryl group), (A4) A substituted 5-14 member aromatic heterocyclic group, (A5) A substituted 3-14 member non-aromatic heterocyclic group, or (A6) A substituted C 4-6 Represents an alkyl group.

[0067] L 1 is, (L 1 1) Single bond, (L 1 2) It may be linked to a divalent group (amide bond) derived from the carbamoyl group, and / or to an ether bond or a thioether bond, C1-3 Alkylene group, (L 1 3) A divalent group derived from a carbamoyl group (amide bond), which may be linked to a divalent group derived from an amino group, (L 1 4) Sulfonyl group, or (L 1 5) C 1-3 Alkenylene group (carbon-carbon double bond is L) 2 It may be formed between adjacent carbon atoms of B or C.

[0068] B may be replaced by (B1), and / or C 1-3 (B2) A divalent group derived from a carbamoyl group (amide bond) which may be linked to a divalent group derived from an alkyl-carbonyl group, (B3) A divalent group derived from a substituted 5-14 member aromatic heterocycle, (B4) A divalent group derived from a substituted 3-14 member non-aromatic heterocycle, (B4) A substituted C 3-10 Cycloalkyl groups, (B5) may be substituted C 3-10 (B6) represents a cycloalkenyl group, (B7) an optionally substituted 6-14 member aromatic hydrocarbon ring group (aryl group), (B8) an ester bond or thioester bond, or (B8) a keto group or thioketo group.

[0069] L 2 is, (L 2 1) Single bond, (L 2 2) C 1-6 Alkylene group, or (L 2 3) C 1-3 Alkenylene group (carbon-carbon double bond is L) 2 It may be formed between adjacent carbon atoms of B or C.

[0070] C is (C1) a divalent group (amide bond) derived from an N-substituted carbamoyl group, (C2) a divalent group derived from an N-substituted 5-14 member aromatic heterocycle, (C3) a divalent group derived from an N-substituted 3-14 member non-aromatic heterocycle, (C4) an N-substituted C 3-10Cycloalkyl groups, (C5) may be substituted. 3-10 The (C6) represents a cycloalkenyl group, an optionally substituted 6- to 14-membered aromatic hydrocarbon ring group (aryl group), or a (C7) ester bond or thioester bond.

[0071] L 3 is, (L 3 1) Single bond, (L 3 2) A divalent group derived from the carbamoyl group (amide bond) and / or a divalent group derived from the imino group (-N=) may be linked and / or substituted with C 1-3 Alkylene group, (L 3 3) C 1-3 An ether bond or thioether bond may be linked to an alkenylene group, or (L 3 4) Represents a divalent group (amide bond) derived from a carbamoyl group, which may be linked to a divalent group derived from an amino group.

[0072] D may be replaced by C (D1). 3-10 Cycloalkyl groups, (D2) may be substituted C 3-10 Cycloalkenyl group, (D3) optionally substituted 6-14 member aromatic hydrocarbon ring group (aryl group), (D4) optionally substituted 5-14 member aromatic heterocyclic group, (D5) optionally substituted 3-14 member non-aromatic heterocyclic group, or (D6) optionally substituted C 1-3 It is an alkyl group.

[0073] In one embodiment of the present invention, the compound of the present invention is represented by general formula (I) (satisfying the requirements of the second embodiment) and has van der Waals forces or other non-covalent interactions with "predetermined amino acid residues constituting an interaction region" as described herein (satisfying the requirements of the first embodiment). On the other hand, the compound of the present invention may satisfy the requirements of the second embodiment but not the requirements of the first embodiment, or it may satisfy the requirements of the first embodiment but not the requirements of the second embodiment, as long as it exhibits the effects of the present invention.

[0074] A, L in general formula (I) 1 , B, L 2 , C, L 3 Preferred specific examples of D include those represented by any of the structural formulas of compounds (1) to (36) of the present invention, and more preferred specific examples include those represented by any of the structural formulas of compounds (1), (2), (5), (9), or (11) of the present invention.

[0075] Of the compounds (1) to (36) shown in Table 2 below, compounds (18), (32), and (33) do not completely conform to the definition of the general formula (I) above.

[0076] Compound (18) is A, L 1 And B together form a unique ring structure (spiro ring) (with substituents), but L 2 , C, L 3 And for D, the definition of general formula (I) can be applied.

[0077] Compound (32) is A, L 1 And B together form a unique ring structure (with substituents), but L 2 , C, L 3 And for D, the definition of general formula (I) can be applied.

[0078] Compound (33) is L 1 , B and L2 These combine to form a predetermined structure (alkylene group), but A, C, L 3 And for D, the definition of general formula (I) can be applied.

[0079] In one embodiment of the present invention, compound (I) has at least a site with which hydrogen bonding or CH-π interaction occurs with Cys154. This site is site L in compound (I). 2 Preferably, it is at least one location selected from the group consisting of A, B, and C, for example, L 2 It is preferable to include both locations B and C. The proton donor (δ+) hydrogen atom may be present in compound (I) or in Cys154.

[0080] For example, compound (I) has a site where hydrogen bonding or CH-π interaction occurs with Cys154, The part A (A6) having a group that acts as a donor or acceptor for a hydrogen atom (or may have such a group as a substituent); The (L) has a group that acts as a donor or acceptor for a hydrogen atom (it may have such a group as a substituent). 1 2) The aforementioned part L 1 ; The site B is (B1) or (B3) having a group that acts as a donor or acceptor for a hydrogen atom (or may have such a group as a substituent); The (C1), (C2), or (C3), (C6), or (C7) moiety C having a group that acts as a donor or acceptor for a hydrogen atom (or may have such a group as a substituent); The (L) has a group that acts as a donor or acceptor for a hydrogen atom (it may have such a group as a substituent). 1 2) or (L 1 4) Part L 1 ; The (L) has a group that acts as a donor or acceptor for a hydrogen atom (it may have such a group as a substituent).2 2) Part L 2 ; The (L) has a group that acts as a donor or acceptor for a hydrogen atom (it may have such a group as a substituent). 3 2) Part L 3 ;or The (C2) or (C6) portion C, which has π electrons (may be possessed by some of the rings in the fused ring which is non-aromatic as a whole), It may have at least one of the following.

[0081] A specific example of a hydrogen bond acting between compound (I) and Cys154 is: Parts B, C, L 1 Hydrogen bonds between the nitrogen atom (lone pair) of -NH-, the oxygen atom (lone pair) of -CO-, the sulfur atom (lone pair) of -S-, etc., contained in these compounds, and the hydrogen atom of -SH contained in the side chain of Cys154 (e.g., compounds (1), (2), (5), (9), (11), (36)); Parts B, L 1 , L 3 Hydrogen bonds are formed between the oxygen atom (lone pair of electrons) of =O contained in, etc., and the hydrogen atom of -SH contained in the side chain of Cys154 (e.g., compounds (7), (14), (15), (24), (25), (26), (31), (35)); A hydrogen bond is formed between the hydrogen atom of the -OH group in site A and the sulfur atom (lone pair of electrons) of the -SH group in the side chain of Cys154 (e.g., compound (11)); Parts B, L 1 , L 2 Examples include hydrogen bonds between hydrogen atoms such as -CH-, -CH2-, -CH(R)- contained in the above, or hydrogen atoms of -NH- contained in B, and sulfur atoms (lone pairs of electrons) of -SH contained in the side chain of Cys154 (e.g., compounds (6), (8), (10), (16), (27), (35)). Furthermore, a specific example of the CH-π interaction between compound (I) and Cys154 is: Examples include CH-π interactions between the π electrons of the aromatic heterocycle (C2) or aromatic hydrocarbon group (C6) contained in site C and the hydrogen atoms of the -SH group contained in the side chain of Cys154 (e.g., compounds (11), (22), (23), (27)). The hydrogen bond or CH-π interaction between compound (I) and Cys154 may be any other intermolecular interaction as shown in Figures 2-36.

[0082] Compound (I) may have sites where hydrogen bonds, CH-π interactions, ionic bonds, or other intermolecular interactions occur with certain amino acid residues other than Cys154 that constitute the interaction region. Typical examples of such intermolecular interactions include sites where hydrogen bonds occur with Asp121, sites where CH-π interactions occur with Pro122, sites where CH-π interactions occur with Asp123, sites where ionic or hydrogen bonds occur with Lys160, sites where CH-π interactions occur with Ser170, and other intermolecular interactions shown in Figures 2 to 36.

[0083] A typical example of a site where hydrogen bonding occurs with Asp121 is the substituted C in (A6), for example, compound (9). 4-6 A part of the alkyl group is part A. C in this embodiment 4-6 The substituents of the alkyl group may contain an atom that acts as a donor or acceptor for forming a hydrogen bond with the asparagine residue, for example, an amino group which may be substituted. Also, among (A1) to (A6) defined as site A, a substituted C 4-6 Other than alkyl groups (corresponding to A6), for example, the -NH- of (A4) in compound (4), and the (L) of compound (29) 1 It is also possible to use groups (A1) to (A5) that have a substituent containing an atom that acts as a hydrogen bond donor or acceptor, such as the -NH- in (2) and the -OH in (A3) of compound (34), as sites where hydrogen bonds are formed with Asp121.

[0084] Representative examples of sites where CH-π interactions occur with Pro122 include site A, which is a divalent group derived from an optionally substituted aromatic heterocycle, such as (A4) in compounds (1) and (28), or a divalent group derived from an optionally substituted non-aromatic heterocycle (provided that it has an aromatic ring (π electrons) as part of a fused ring), such as (A5) in compound (33). The aromatic heterocycle or non-aromatic heterocycle in this embodiment may be any group having π electrons that can form a CH-π interaction with a proline residue. Furthermore, among the (A1) to (A6) defined as site A, it is also possible to use a cyclic group other than (A4) and (A5), such as (A3) which has π electrons, as the site where CH-π interactions occur with Pro122.

[0085] Furthermore, hydrogen bonds may form between compound (I) of the present invention and Pro122. Examples of sites that generate such hydrogen bonds include site B, which is (B5) in compounds (12), (13), and (17), i.e., a divalent group derived from a substituted cycloalkenyl group, and site B, which is (B3) in compound (19), i.e., a divalent group derived from a substituted non-aromatic heterocycle. In this embodiment, the substituents on the cycloalkenyl group or heterocycle may contain an atom that acts as a donor or acceptor for forming a hydrogen bond with the proline residue, for example, a hydroxyl group. In addition, among the (B1) to (B8) defined as site B, it is also possible to use sites other than (B3) and (B5), such as the groups (B1), (B2), (B4), (B6) to (B8) that have atoms that act as hydrogen bond donors or acceptors as substituents, as sites where hydrogen bonds form with Pro122.

[0086] A typical example of a site where a CH-π interaction occurs with Asp123 is site A, which is a non-aromatic heterocyclic group (which may be substituted) of compound (2), for example, (A5). In this embodiment, the non-aromatic heterocyclic group is a group having π electrons so that a CH-π interaction can be formed with the aspartic acid residue, for example, a fused ring of an aromatic ring and a non-aromatic ring (which is non-aromatic overall, but has π electrons in the aromatic ring portion, so a CH-π interaction can be formed with the aspartic acid residue in that portion). In addition, among (A1) to (A6) defined as site A, any group other than (A5), for example, a cyclic group (A3) or (A4) having π electrons, can also be used as a site where a CH-π interaction occurs with Asp123.

[0087] Furthermore, hydrogen bonds may form between compound (I) of the present invention and Asp123. Examples of sites that generate such hydrogen bonds include site C, which is (C6) of compound (27), i.e., an optionally substituted aromatic hydrocarbon group, or site C, which is (C8) of compound (34), i.e., a methylene group substituted with an optionally substituted hydroxyl group. The substituents of the aromatic hydrocarbon group or methylene group in this embodiment only need to contain an atom that acts as a donor or acceptor for forming a hydrogen bond with the proline residue, such as a hydroxyl group (or a substituent having a hydroxyl group at its terminus). In addition, among the (C1) to (C8) defined as site C, it is also possible to use a group other than (C6) and (C8), such as (C1) to (C5) or (C7) which has an atom that acts as a hydrogen bond donor or acceptor as a substituent, as a site where a hydrogen bond forms with Pro122.

[0088] Representative examples of sites where ionic or hydrogen bonds are formed with Lys160 include, for example, site D of compound (1), i.e., the (D1), i.e., the substituted cycloalkyl group; site D of compound (5), i.e., the substituted aromatic hydrocarbon ring group; site D of compound (6), i.e., the substituted non-aromatic heterocyclic group; site D of compounds (21), (23), and (31), i.e., the optionally substituted aromatic heterocyclic group; or site D of compound (32), i.e., the optionally substituted alkyl group; and site L of compound (24). 3 2) An example is an alkylene group which may be linked to a predetermined group or substituted by a predetermined group. The substituents of the cycloalkyl group and aromatic hydrocarbon ring group in this embodiment may contain an atom that generates an anion for forming an ionic bond with the lysine residue or an atom that acts as a donor or acceptor for forming a hydrogen bond. An example of the former is a carboxyl group, and an example of the latter is a keto group (oxo group). In addition, among the (D1) to (D6) defined as site D, it is also possible to use a group other than (D1), (D3) and (D5), such as (D2), (D4) or (D6) having the above substituents, as a site where an ionic bond or hydrogen bond is formed with Lys160.

[0089] Furthermore, a cation-π interaction may occur between compound (I) of the present invention and Lys160. Examples of sites that give rise to such cation-π interactions include (D3) of compound (33), i.e., site D, which is an aromatic hydrocarbon group (phenyl group) that may be substituted. The aromatic hydrocarbon group in this embodiment is a group having π electrons that can form a cation-π interaction with the lysine acid residue. In addition, among (D1) to (D8) defined as site D, it is also possible to use sites other than (D3), such as (D4) which has π electrons, or (D5) in embodiments that are non-aromatic overall but have π electrons in the aromatic ring portion, as sites that give rise to cation-π interactions with Lys160.

[0090] Examples of sites where CH-π interactions occur with Ser170 include site D, which is (D3) in compounds (2), (12), (13), (17), (19), (27), and (29), i.e., an aromatic hydrocarbon group that may be substituted, or site D, which is (D5) in compounds (9), (15), and (16), i.e., an unaromatic heterocyclic group that may be substituted (provided that it has an aromatic ring (π electrons) as part of the fused ring). In this embodiment, the aromatic hydrocarbon group can be any group having π electrons that can form a CH-π interaction with a serine residue. In this embodiment, the unaromatic heterocyclic group can be any group having π electrons that can form a CH-π interaction with a serine residue, for example, a fused ring of an aromatic ring and an unaromatic ring (which is unaromatic as a whole, but has π electrons in the aromatic ring portion, so a CH-π interaction can be formed with the serine residue in that portion). Furthermore, among the sites (D1) to (D6) defined as site D, it is also possible to designate sites other than (D3) and (D5), such as the cyclic group (D4) having π electrons, as sites where CH-π interactions occur with Ser170.

[0091] In addition, compound (I) may have at least one selected from the group consisting of a hydrogen bond with Gln124, a hydrogen bond with Asp153, a hydrogen bond with Glu155, a hydrogen bond with Ser168, a hydrogen bond with Ser258, a hydrogen bond with Asp262, a hydrogen bond with Leu264, or a CH-π interaction and a hydrogen bond with His266. The sites where predetermined interactions occur with these predetermined amino acid residues can be defined from the drawings or tables in the same manner as in the embodiments described above.

[0092] Compound (I) may contain stereoisomers, i.e., enantiomers (mirror-image isomers) and / or diastereomers (stereoisomers other than enantiomers). In the present invention, compound (I) may be a mixture of stereoisomers (for example, a racemic mixture of enantiomers), or a purified product with increased purity of a specific stereoisomer useful for pharmacological activity may be used, for example, a purified product with a purity of 90% or higher, preferably 95% or higher, more preferably 99% or higher, and ideally consisting substantially only of that stereoisomer.

[0093] Compound (I) may contain tautomers. An example of a tautomer is the ketoenol tautomer, which has interconvertible structures as shown below. Regardless of which structure is represented by general formula (I), all tautomers can be included in compound (I).

[0094] [ka]

[0095] Each part of compound (I) may be ionized under the conditions under which compound (I) is used, typically under physiological conditions. For example, the carboxyl group (-COOH) may be ionized by the carboxylate ion (-COO). - It may exist in the state of ).

[0096] In one embodiment of the present invention, compound (I) is one of compounds (1) to (36) shown in Table 2. Compound (3) represents a racemic mixture of the S and R isomers, while compound (1) represents only the S isomer. The docking score "GBVIWSA_dG" (negative value, unit kcal / mol) indicates that a smaller value means that the compound and IL-17RA bind more stably. Regarding the "total number" shown in parentheses in "number of amino acid residues where non-covalent interactions other than van der Waals forces act," for example, if two non-covalent interactions other than van der Waals forces (intermolecular interactions) act on one amino acid residue, the total number will be "2," and it can also be said to represent the "total number of non-covalent interactions other than van der Waals forces (intermolecular interactions)." For compounds (1) to (36) excluding compound (3), Table 3 shows the interacting amino acid residues that constitute the interaction region.

[0097] For reference, regarding the cyanidin compound (A18, see Chemical Formula 1) described in Non-Patent Document 3 above, the GBVIWSA_dG value when it is configured to interact with Asp121, Gln124, Ser168, and Asp262 as described in the document is -5.3894 kcal / mol, which is larger than any of the GBVIWSA_dG values ​​of compounds (1) to (36) shown in the table below (the maximum is compound (36) at -7.5007 kcal / mol), suggesting poor binding stability.

[0098] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

Table 2-7

[0099]

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

[0100] In the present invention, derivatives of Compounds (1) to (36) can also be used as IL-17A activity inhibitors. A person skilled in the art can prepare derivatives of Compounds (1) to (36) and select derivatives having a desired IL-17A activity inhibitory ability without excessive trial and error, and implement the present invention. For example, by referring to the descriptions of the derivatives of Compounds (1), (5), (9), and (11) described below, and also by referring to the content shown in the schematic diagrams representing the modes of non-covalent interactions between each compound and the amino acid residues contained in the extracellular domain of IL-17RA shown in the drawings, derivatives that can be used in the present invention can be similarly prepared from other compounds.

[0101] When preparing derivatives, the groups, bonds, and other structures to be replaced from the original compound may be selected from the same types as those present in the original compound, or from different types. In this specification, for structural formula (I), there are 6 types for site A (A1) to (A6), 8 types for site B (B1) to (B8), 7 types for site C (C1) to (C7), and 6 types for site D (D1) to (D6). 1 as (L 1 1)~(L 1 5) 5 types, L 2 as (L 2 1)~(L 2 3) Three types, L 3 as (L 3 1)~(L 3 4) Four types are given as examples, and specific examples are also provided. For example, if the original compound has a group (A1) as site A, the derivative can have a different group selected from (A1) (same type) as the site corresponding to site A, a group selected from (A2) to (A6) (different type), or a group selected from types other than (A1) to (A6). The same applies to other sites. Furthermore, when creating a derivative, if a substituent different from the original compound is to be used, or if a substituent that was not present in the original compound is to be introduced, the substituent for the derivative can be selected from those exemplified as "substituent group A" in this specification.

[0102] In one embodiment of the present invention, a derivative of a certain compound is a compound with sites A and L 1 , B, L 2 , C, L 3 Of the seven sites of D, four, five, or six sites are identical to the original compound, and the remaining sites are other groups selected from the same type as the original compound (e.g., with different substituents), or groups selected from a different type than the original compound. In one embodiment of the present invention, a derivative of a certain compound is sites A, L 1 , B, L 2 , C, L 3And of the seven sites of D, four, five, six, or seven sites are the same group as the original compound or other groups selected from the same type (except when all seven sites are the same group), and the remaining sites are groups selected from a different type than the original compound. In one embodiment of the present invention, "other groups selected from the same type as the original compound" or "groups selected from a different type than the original compound" are, in their respective corresponding sites, groups possessed by compounds other than the original compound among compounds (1) to (36).

[0103] In one embodiment of the present invention, if the original compound has a cyclic structure in a certain part, the derivative of the compound also has a cyclic structure in the corresponding part. In one embodiment of the present invention, if the original compound has a chain-like structure in a certain part, the derivative of the compound also has a chain-like structure in the corresponding part.

[0104] In one embodiment of the present invention, if the original compound has a cyclic or chain-like structure at a certain site, the derivatives of the compound have a chain-like or cyclic structure at the corresponding site, according to the mutual conversion of cyclic and chain-like structures used in pharmaceuticals. In one embodiment of the present invention, if the original compound has a cyclic or chain-like structure with substituents at a certain site, the derivatives of the compound have a chain-like or chain-like structure at the corresponding site, each having substituents with the same or similar chemical properties.

[0105] Generally, it is preferable that the non-covalent interactions between the derivatives of compounds (1) to (36) and IL-17RA are, in their entirety (summary), more stable (stronger) than the non-covalent interactions between each of the original compounds (1) to (36) and IL-17RA. As an indicator of the stability (strength) of such interactions, for example, the score (unit kcal / mol) shown as "GBVIWSA_dG" in Table 2 can be referred to. If necessary, the structures to be introduced into the derivatives can be selected while referring to indicators of the stability (strength) of van der Waals forces and / or non-covalent interactions other than van der Waals forces.

[0106] However, when preparing derivatives of compounds (1) to (36), it is desirable to modify the structures of compounds (1) to (36) to approach the desired properties, taking into account not only the enhanced binding stability with IL-17RA, but also, for example, solubility in solvents and pharmacokinetics, which are important for use as active ingredients in pharmaceuticals. Various known techniques in the technical field related to this invention can be used when preparing derivatives.

[0107] Of compounds (1) to (36), all except compound (3), the structures A and L in the general formula (I) of each compound. 1 , B, L 2 , C, L 3 Table 4 shows the parts corresponding to and D. In a preferred embodiment of the present invention, compound (I) is compound (1), (2), (5), (9), or (11), or a derivative thereof. For example, derivatives of compound (1), (2), (5), (9), or (11) are A, L 1 , B, L 2 , C, L 3 And four, five, or six of the D groups may be the same groups as the original compound, and the remaining groups may be other groups selected from the same type as the original compound, or groups selected from a different type than the original compound. Also, derivatives of compounds (1), (2), (5), (9), or (11) may be A, L 1 , B, L2 , C, L 3 Four, five, six, or seven sites out of C, L, and D are groups selected from the same groups as the original compound or other groups of the same type (except when all seven sites are the same group), and the remaining sites may be groups selected from a different type than the original compound. The same applies to compounds other than compounds (1), (2), (5), (9), and (11).

[0108] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] <​​​​​​​​​​​​​​​​​​​​​​​​ As shown in Figure 2, compound (1) can stably bind within the interaction region through van der Waals forces acting between it and certain amino acid residues constituting the interaction region, specifically Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, and Leu264, as well as through non-covalent interactions other than van der Waals forces acting between it and some of these amino acid residues. In general formula (I), the "phthalazine ring" (benzene ring portion of the fused ring) in site A is the part that forms a CH-π interaction with Pro122, the two "carbamoyl groups" (amide bonds) in sites B and C respectively form hydrogen bonds with Cys154 (acting as donors), and the "(ionized) carboxyl group as a substituent on the cyclohexyl group" in site D forms an ionic bond with the ionized amino group of Lys160.

[0112] As one embodiment of a derivative of compound (1), a derivative (1-X) is obtained by modifying the original compound (1) such that the van der Waals forces between Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, and Leu264 are enhanced compared to compound (1).

[0113] The dotted lines in Figure 2 (and other figures) represent the contact surfaces between the atoms of compound (1) (and other compounds of the present invention) and the atoms of the surrounding amino acid residues. The narrower the distance between the atoms in the structural formula and the dotted line, the tighter the bond; the wider the distance, the looser the bond. Therefore, to make the distance between the atoms in the structural formula and the dotted line narrower, sites A, B, C, D, and L in the structural formula are... 1 , L 2 and L 3The van der Waals forces between compound (1) (and the compound of the present invention) and the above amino acid residues (and other predetermined amino acid residues constituting the interaction region) can potentially be enhanced by modifying the structure of at least one site selected from the group consisting of the above, for example by changing it to a bulkier group or by introducing a substituent.

[0114] As one embodiment of a derivative of compound (1), a derivative (1-Y) is obtained by modifying the original compound (1) to have a site where at least one of the CH-π interaction with Pro122, the hydrogen bond with Cys154, and the ionic bond with Lys160 of compound (1) is enhanced, or a site where at least one non-covalent interaction, different from these (in terms of the type and strength of the intermolecular interaction and at least one of the target amino acid residues), occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, and Leu264.

[0115] A derivative (1-Y) modified from the above perspective may be, for example, the following: A derivative in which the stability of the CH-π interaction with Pro122 is improved by modifying site A (the phthalazine ring substituted with a hydroxyl group) in general formula (I); Derivatives in which the stability of hydrogen bonding with Cys154 is improved by modifying sites B and / or C (both carbamoyl groups) in general formula (I); A derivative in which the stability of the ionic bond with Lys160 is improved by modifying site D (a carboxyl-substituted cyclohexyl group) in general formula (I); In addition, parts A and L in general formula (I) 1 , B, L 2 , C, L 3By modifying D, derivatives are produced that generate new non-covalent interactions with Asp121, Gln124, Glu155, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, or Leu264 (amino acid residues other than Pro122, Cys154, and Lys160), and also with other predetermined amino acid residues constituting the interaction region.

[0116] As one embodiment of a derivative of compound (1), a derivative (1-Z) is obtained by modifying the original compound (1) to have a site that reduces the exposure of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Ser258, Cys259, Asp262, Cys263, and Leu264 to the solvent side, compared to compound (1).

[0117] In Figure 2 (and other figures), the shadows around the circles representing amino acid residues constituting the interaction region indicate that exposure to the solvent side is reduced by the binding of compound (1) (and other compounds of the present invention). The larger the shadow, the greater the degree of reduction (see, for example, Leu264 in Figure 2). Amino acid residues with reduced exposure to the solvent side exhibit stronger hydrophobic interactions with the compounds of the present invention, and the binding of IL-17A to IL-17RA is competitively and more strongly inhibited.

[0118] A derivative of compound (1) may simultaneously satisfy two or all three of the conditions related to (1-X), (1-Y), and (1-Z).

[0119] Compound (2) is the compound represented by the following structural formula (2).

[0120] [ka]

[0121] As shown in Figure 3, compound (2) can stably bind within the interaction region through van der Waals forces acting between it and certain amino acid residues constituting the interaction region, specifically Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, Pro254, Phe256, Ser258, Cys259, Asp262, Leu264, and His266, as well as through non-covalent interactions other than van der Waals forces acting between it and some of these amino acid residues. In general formula (I), the ring in site A (the benzene ring portion of the fused ring) forms a CH-π interaction with Asp123, the carbamoyl group in site B forms a hydrogen bond with Cys154 (acting as a donor), and the phenyl group in site D (substituted with two methoxy groups) forms a CH-π interaction with Ser170.

[0122] One embodiment of a derivative of compound (2) is a derivative (2-X) obtained by modifying the original compound (2) such that the van der Waals forces between it and Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, Pro254, Phe256, Ser258, Cys259, Asp262, Leu264, and His266 are enhanced compared to compound (2).

[0123] As one embodiment of a derivative of compound (2), a derivative (2-Y) is obtained by modifying the original compound (2) to have a site where at least one of the CH-π interactions of compound (2) with Asp123, a hydrogen bond with Cys154, or a CH-π interaction with Ser170 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, Pro254, Phe256, Ser258, Cys259, Asp262, Leu264, and His266.

[0124] As one embodiment of a derivative of compound (2), a derivative (2-Z) is obtained by modifying the original compound (2) to have a site that reduces the exposure of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Pro164, Ser168, Gly169, Ser170, Trp172, Pro254, Phe256, Ser258, Cys259, Asp262, Leu264, and His266 to the solvent side compared to compound (2).

[0125] Compound (5) is the compound represented by the following structural formula (5).

[0126] [ka]

[0127] As shown in Figure 5, compound (5) can stably bind within the interaction region through van der Waals forces acting between it and certain amino acid residues constituting the interaction region, specifically Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264, and His266, as well as through non-covalent interactions other than van der Waals forces acting between it and some of these amino acid residues. In general formula (I), the keto group (oxo group as a substituent) in site B forms a hydrogen bond with Cys154 (acting as an acceptor), and the keto group (oxo group bonded to the carbon atom of the pyrrolidine ring as a substituent of the phenyl group (substituting a hydrogen atom)) in site D forms a hydrogen bond with Lys160 (acting as an acceptor).

[0128] As one embodiment of a derivative of compound (5), a derivative (5-X) is obtained by modifying the original compound (5) such that the van der Waals forces between it and Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264, and His266 are enhanced compared to compound (5).

[0129] As one embodiment of a derivative of compound (5), a derivative (5-Y) is obtained by modifying the original compound (5) to have a site where at least one hydrogen bond with Cys154 or Lys160 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264, and His266.

[0130] As one embodiment of a derivative of compound (5), a derivative (5-Z) is obtained by modifying the original compound (5) to have a site that reduces the exposure of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Cys263, Leu264, and His266 to the solvent side compared to compound (5).

[0131] Compound (9) is the compound represented by the following structural formula (9).

[0132] [ka]

[0133] As shown in Figure 9, compound (9) can stably bind within the interaction region through van der Waals forces acting between it and certain amino acid residues constituting the interaction region, specifically Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266, as well as through non-covalent interactions other than van der Waals forces acting between it and some of these amino acid residues. In general formula (I), the substituted amino group in site A forms a hydrogen bond with Asp121 (acting as a donor), the keto group (oxo group as a substituent) of the ring in site B forms a hydrogen bond with Cys154 (acting as an acceptor), and the ring (benzene ring portion of the fused ring) in site D forms a CH-π interaction with Ser170.

[0134] One embodiment of a derivative of compound (9) is a derivative (9-X) obtained by modifying the original compound (9) such that the van der Waals forces between it and Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 are enhanced compared to compound (9).

[0135] As one embodiment of a derivative of compound (9), a derivative (9-Y) is obtained by modifying the original compound (9) to have a site where at least one of the CH-π interactions of compound (9) with Asp121, a hydrogen bond with Cys154, or a CH-π interaction with Ser170 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs between the original compound (9) and at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266.

[0136] As one embodiment of a derivative of compound (9), a derivative (9-Z) is obtained by modifying the original compound (9) to have a site that reduces the exposure of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Asp123, Asp153, Cys154, Glu155, Lys160, Pro164, Ser167, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 to the solvent side, compared to compound (9).

[0137] Compound (11) is the compound represented by the following structural formula (11).

[0138] [ka]

[0139] As shown in Figure 11, compound (11) can stably bind within the interaction region through van der Waals forces acting between it and certain amino acid residues constituting the interaction region, specifically Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266, as well as through non-covalent interactions other than van der Waals forces acting between it and some of these amino acid residues. In general formula (I), the hydroxyl group in site A forms a hydrogen bond with Cys154 (acting as a donor), the carbamoyl group (oxygen atom) in site B forms a hydrogen bond with Cys154 (acting as an acceptor), and the ring in site C forms a CH-π interaction with Cys154.

[0140] As one embodiment of a derivative of compound (11), a derivative (11-X) is obtained by modifying the original compound (11) such that the van der Waals forces between it and Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 are enhanced compared to compound (11).

[0141] As one embodiment of a derivative of compound (11), a derivative (11-Y) is obtained by modifying the original compound (11) to have a site where at least one CH-π interaction or hydrogen bond with Cys154 is enhanced, or a site where at least one non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266.

[0142] As one embodiment of a derivative of compound (11), a derivative (11-Z) is obtained by modifying the original compound (11) to have a site that reduces the exposure of at least one amino acid residue selected from the group consisting of Asp121, Pro122, Gln124, Asp153, Cys154, Glu155, Pro164, Cys165, Ser168, Gly169, Ser170, Trp172, Ser258, Cys259, Asp262, Leu264, and His266 to the solvent side, compared to compound (11).

[0143] Derivatives of compounds other than compounds (1), (2), (5), (9), and (11) can be derived in the same manner based on the information shown in the drawings and tables. That is, if we define "P" as the set of amino acid residues that constitute the interaction region and which are subject to van der Waals forces with the original compound, and "Q" as the set of amino acid residues that are subject to non-covalent interactions other than van der Waals forces with the original compound, then derivatives of each compound include those obtained by modifying the original compound to satisfy at least one condition selected from the group consisting of [x], [y], and [z] below. [x] Compared to the original compound, the van der Waals forces of the sum of the amino acid residues of aggregate P are enhanced; [y] Having a site where non-covalent interactions other than van der Waals forces with at least one amino acid residue selected from the group consisting of set Q, which are present in the original compound, or a site where a different non-covalent interaction other than van der Waals forces occurs with at least one amino acid residue selected from the group consisting of set P; [z] The compound has a site that reduces the exposure of at least one amino acid residue selected from the group consisting of set P to the solvent side compared to the original compound.

[0144] Compound (I) may be in the form of a pharmaceutically acceptable salt, solvate, or prodrug. In this specification, Compound (I) (the compound represented by general formula (I)) and its pharmaceutically acceptable salts, solvates, and prodrugs may be collectively referred to as "the compound of the present invention."

[0145] A pharmaceutically acceptable salt means that, when used as an active ingredient in a medicine, the salt of that compound is not harmful for therapeutic, preventive, or other purposes. Examples of pharmaceutically acceptable salts include: Examples of basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, and brocaine salt; aralkylamine salts such as N,N-dibenzylethylenediamine; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, and isoquinoline salt; quaternary ammonium salts such as tetramethylammonium salt, tetraethylamonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, and tetrabutylammonium salt; and basic amino acid salts such as arginine salt and lysine salt. Examples of acidic salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and perchlorate; organic acid salts such as acetate, propionate, lactate, maleate, fumarate, tartrate, malate, citrate, and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate; and acidic amino acids such as aspartate and glutamate.

[0146] A solvate is typically a hydrate, and may be a single solvate (monohydrate), a double solvate (dihydrate), or a larger number of solvates (hydrates).

[0147] A prodrug is a derivative having a group that can be chemically or metabolically degraded, and which becomes a pharmaceutically active compound by solvolysis (e.g., decomposition in phosphate buffer (pH 7.4)-ethanol) or under physiological conditions (in vivo).

[0148] Examples of prodrugs of carboxylated compounds include ester derivatives produced by reacting the original acidic compound with a suitable alcohol, or amide derivatives produced by reacting the original acidic compound with a suitable amine. Particularly preferred esters as prodrugs include methyl esters, ethyl esters, n-propyl esters, isopropyl esters, n-butyl esters, isobutyl esters, tert-butyl esters, morpholinoethyl esters, and N,N-diethyl glycolamide esters.

[0149] Examples of prodrugs of hydroxyl compounds include acyloxy derivatives produced by reacting a compound having a hydroxyl group with a suitable acyl halide or suitable acid anhydride. Particularly preferred acyloxy as prodrugs are -O(=O)-CH3, -OC(=O)-C2H5, -OC(=O)-(tert-Bu), and -OC(=O)-C 15 H 31 Examples include -OC(=O)-(m-COONa-Ph), -OC(=O)-CH2CH2COONa, -O(C=O)-CH(NH2)CH3, and -OC(=O)-CH2-N(CH3)2.

[0150] Examples of prodrugs of amino compounds include amide derivatives produced by reacting the original amino compound with a suitable acid halide or a suitable mixed acid anhydride. Particularly preferred amides as prodrugs include -NHC(=O)-(CH2) 20 Examples include CH3, -NHC(=O)-CH(NH2)CH3, etc.

[0151] The applications of the IL-17 activity inhibitor of the present invention are not particularly limited, and it can be used in various in vitro, ex vivo, or in vivo settings, depending on the purpose of inhibiting the binding of IL-17 to IL-17RA, typically IL-17RA (extracellular domain) expressed on the cell surface.

[0152] In one embodiment of the present invention, the IL-17 activity inhibitor is used as an expression regulator (or as a component thereof when the expression regulator is prepared as a composition) as described later.

[0153] In one embodiment of the present invention, the IL-17 activity inhibitor is used as a pharmaceutical (or as an active ingredient if the pharmaceutical is prepared as a composition) as described later. In other words, in one embodiment of the present invention, the IL-17 activity inhibitor is used to manufacture a pharmaceutical (pharmaceutical composition) as described later.

[0154] In one embodiment of the present invention, the IL-17 activity inhibitor is used in a method for inhibiting the binding of IL-17A to IL-17RA, as described later.

[0155] —Expression regulators— In one aspect of the present invention, the "expression regulator" provided is an agent for regulating the expression level of a gene whose expression level changes upon binding of IL-17A to IL-17RA in cells expressing IL-17RA, and contains the IL-17A activity inhibitor of the present invention as described above.

[0156] The term "genes whose expression level changes upon binding of IL-17A to IL-17RA" is not particularly limited and includes, for example, genes whose expression level increases or decreases (is enhanced or suppressed) due to signal transduction reactions as shown in Figure 45.

[0157] In a typical embodiment of the present invention, the gene whose expression level changes upon binding of IL-17A to IL-17RA is a gene whose expression is upregulated upon binding of IL-17A to IL-17RA. It is widely known that IL-17A is an inflammatory cytokine and that binding to IL-17RA induces the expression of signaling molecules (proteins such as cytokines, chemokines, and growth factors) that cause inflammation, etc. (see, for example, the aforementioned Patent Document 2).

[0158] In a typical embodiment of the present invention, the gene whose expression is upregulated by the binding of IL-17A to IL-17RA is at least one selected from the group consisting of IL-6, COX-2, mPGES1, MMP-3, MMP-13, and CXCL1. These genes are deeply involved in symptoms such as intervertebral disc degeneration. The fact that the expression of these genes is upregulated by the binding of IL-17A to IL-17RA, and that the compounds of the present invention can inhibit this binding and reduce the expression level of the above genes, is demonstrated in the examples described below.

[0159] IL-6 is known as a cytokine that works in cooperation with TGFβ to induce IL-17A expression by Th17 cells (Ivanov, II et al., Cell 126, 1121-1133, 2006; Gaffen, SL, Current opinion in immunology 23, 613-619, 2011). It has also been reported that IL-6 is secreted in the intervertebral disc even in the absence of macrophages (Rand et al., Spine 22, 2598-2601, 1997), and that its expression level is elevated in cells with herniated discs (Andrade, P. et al., European spine journal 22, 714-720, 2013). Furthermore, IL-6 reduces the production of extracellular matrix in the intervertebral disc, accelerating degeneration (Kang, JD et al., Spine 21, 271-277, 1996; Phillips, KL et al., Arthritis research & therapy 15, R213, 2013; Studer. RK et al., Spine 36, 593-599, 2011; Patel, KP et al., Spine 32, 2596-2603, 2007), and contributes to the expression of inflammatory mediators such as TNFα and PGE-2 (Phillips, KL et al., 2013; Patel, KP et al., 2007), causing neuropathic pain (Murata, Y. et al., Spine 36, 926-932, 2011; Murata, Y., et al., Spine 33, 155-162, 2008) also demonstrates this. Therefore, IL-6 plays an important role in the progression of nucleus pulposus cell degeneration and the symptoms associated with degenerative diseases, and suppressing its expression can be expected to suppress the progression of intervertebral disc degeneration and alleviate symptoms associated with degenerative diseases.

[0160] COX-2 (cyclooxygenase-2) is known to be a key enzyme in the biosynthesis of prostaglandins in intervertebral disc cells (Miyamoto et al., Spine 27, 2477-2483, 2002; van Dijk. B. et al., Journal of orthopaedic research 33, 1724-1731, 2015), and its biosynthesis is induced by mechanical stress, triggering a degenerative cascade (Seibert, K. et al., Proceedings of the National Academy of Sciences of the United States of America 91, 12013-12017, 1994; Williams, CS et al., Oncogene 18, 7908-7916, 1999). Furthermore, it has been reported that IL-6 is involved in COX-2 production (Studer. RK et al, 2011; van Dijk. B. et al., 2015). Therefore, suppressing COX-2 expression can also be expected to have effects such as suppressing the progression of intervertebral disc degeneration and alleviating symptoms associated with degenerative diseases.

[0161] mPGES1 (microsomal prostaglandin E synthase-1) selectively interacts with COX-2 to produce PGE2 (prostaglandin E2). PGE2 hypersensitizes nerves and exacerbates lower back pain (Kang, JD et al., 1996, cited above).

[0162] MMP-3 (matrix metalloproteinases-3) and MMP-13 (matrix metalloproteinases-13) are proteins also known as stromemycin-1 and collagenase-3, respectively. When these proteins degrade extracellular matrix components such as collagen fibers and hydrophilic proteoglycans, the degeneration process of intervertebral discs is accelerated (Antoniou, J. et al., The Journal of Clinical Investigation 98, 996-1003, 1996).

[0163] CXCL1 is one of the chemokines that induces neutrophil activation and migration and is involved in the formation of inflammation (Charo et al., N Engl J Med. 354, 610-621, 2006), and is produced by macrophages, mast cells, and keratinocytes (De Filippo et al., Blood. 121, 4930-4937, 2013; Lowes et al., Trends Immunol. 34.174-181, 2013). CXCL1 production by these cells is also induced by IL-17A stimulation (Iwakura et al., Immunity. 34, 149-162, 2011). In the pathogenesis of psoriasis, IL-17A acts on keratinocytes to promote CXCL1 production, leading to neutrophil infiltration into the stratum corneum of the skin, which is thought to be involved in the formation of microabscesses and contributes to epidermal hyperproliferation and keratinization abnormalities (Girolomoni et al., Br J Dermatol., 167(4), 717-724, 2012; Lin et al., FASEB. 32, 2018). Furthermore, it has been reported that inflammatory cytokine stimulation such as TNFα may activate MAPK factors p38 and JNK, thereby promoting CXCL1 expression (Shieh et al., Cell Physiol Biochem. 34, 1373-1384, 2014).

[0164] In a further embodiment of the present invention, the genes whose expression is upregulated by the binding of IL-17A to IL-17RA are the genes whose expression is upregulated by the phosphorylation of p38. Genes that are presumed to be such include COX-2, IL-6, and CXCL1.

[0165] It has been reported that COX-2 expression is due to the phosphorylation and activation of p38 and JNK (c-Jun N-terminal kinase) by IL-17A in the p38 pathway and JNK pathway, respectively, which are part of the MAPK (mitogen-activated protein kinase) pathway (see Figure 45) (Li. JK et al., Journal of translational medicine 14, 77, 2013). As shown in Example 3 (Figure 43), in the present invention, at least the phosphorylation of p38 can be suppressed by administering an expression regulator, and this is thought to also affect the suppression of the expression of COX-2, IL-6, CXCL1, etc.

[0166] The expression regulator of the present invention is not particularly limited in its use and can be used in various in vitro, ex vivo, or in vivo settings in cells expressing IL-17RA, depending on the purpose of regulating the expression level of genes whose expression level changes upon binding of IL-17A to IL-17RA.

[0167] The expression regulator of the present invention preferably targets cells that express IL-17RA, such as intervertebral disc nucleus pulposus cells or epidermal cells. More preferably, the target of intervertebral disc nucleus pulposus cells is intervertebral disc nucleus pulposus cells cultured under hypoxic conditions (for example, with an oxygen concentration of around 1% in the culture medium atmosphere) or intervertebral disc nucleus pulposus cells present within the intervertebral disc tissue (nucleus pulposus).

[0168] Intervertebral disc nucleus pulposus cells, epidermal cells, and other IL-17RA-expressing cells may be human cells or cells from non-human mammals, such as non-human primates (e.g., cynomolgus monkeys, rhesus monkeys, chimpanzees), cattle, pigs, mice, rats, and other disease model animals. In other words, the expression regulator of the present invention may target human IL-17RA or IL-17RA from non-human mammals (e.g., rats used in the examples). Intervertebral disc nucleus pulposus cells, epidermal cells (keratinocytes, etc.), and other IL-17RA-expressing cells may be primary cells or passaged cells collected from tissues containing IL-17RA-expressing cells, such as intervertebral disc tissue (nucleus pulposus) or skin tissue (epidermis) of humans or non-human mammals, or they may be immortalized cells.

[0169] When culturing IL-17RA-expressing cells in vitro or ex vivo, it is desirable to culture them under conditions as close as possible to the microenvironment of the tissue in which the IL-17RA-expressing cells exist, particularly the microenvironment where symptoms such as inflammation and degeneration occur. For example, intervertebral disc nucleus pulposus cells are preferably cultured under hypoxic conditions similar to those of degenerated intervertebral disc tissue (nucleus pulposus). "Hypoxic conditions" generally refer to conditions where the oxygen concentration of the culture medium atmosphere is 0.5-10%, preferably 1-5%, for example, about 1%. Intervertebral disc nucleus pulposus cells may also be cultured under conditions such as acidity, low glucose (hypoglycemia), and high osmotic pressure, as needed. "Acidic conditions" refer to, for example, a pH range of 6.5-7.4 or less at room temperature (e.g., 25°C) of the culture medium. "Low glucose" refers to, for example, a glucose concentration in the culture medium of 4.5 g / L or less.

[0170] In one embodiment of the present invention, the expression regulator is used as a pharmaceutical product of the present invention (or as an active ingredient if the pharmaceutical product is prepared as a composition), as described later. In other words, in one embodiment of the present invention, the expression regulator is used to manufacture the pharmaceutical product (pharmaceutical composition) of the present invention.

[0171] In one embodiment of the present invention, the expression regulator is used in a method for regulating the expression of a gene whose expression level changes upon binding of IL-17A to IL-17RA, as described later.

[0172] —Medicine for treatment or prevention— A "pharmaceutical for treatment or prevention" provided in one aspect of the present invention is a pharmaceutical containing the IL-17A activity inhibitor or expression inhibitor of the present invention as described above as an active ingredient, for the treatment or prevention of "diseases in which the binding of IL-17A to IL-17RA is associated with symptoms."

[0173] "Treatment" (which may also be called "treatment") refers to any reduction or improvement of a disease, disorder, or condition, including any objective or subjective parameters, such as reducing, alleviating, or decreasing symptoms, or making the disease, disorder, or condition more tolerable to the subject (e.g., by reducing pain or itching), slowing the rate of degeneration or deterioration, mitigating the severity of the endpoint of degeneration or deterioration, improving the subject's physical or mental health, or extending survival. "Prevention" refers to preventing the onset of symptoms, etc. The effects of "treatment" and "prevention" can be evaluated based on objective or subjective parameters, including the results of physical and / or neurological examinations (such as psychiatric evaluations).

[0174] The term "diseases in which the binding of IL-17A to IL-17RA is associated with symptoms" is not particularly limited, but generally includes diseases broadly classified as inflammatory, allergic, or immunological, such as inflammatory skin diseases like psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, and erythrodermic psoriasis; inflammatory joint diseases like ankylosing spondylitis and rheumatoid arthritis; inflammatory bowel diseases like Crohn's disease; autoimmune diseases like Behçet's disease; organ / tissue transplant rejection, sepsis, etc. The pharmaceutical product of the present invention should be formulated to be suitable for delivery to organs, tissues, or cells associated with the symptoms of each disease.

[0175] In a typical embodiment of the present invention, the pharmaceutical product of the present invention is a pharmaceutical product for treating or preventing diseases in which inflammation or degeneration of the intervertebral disc (nucleus pulposus) manifests as symptoms, such as lumbar or cervical disc disease, herniated disc, cervical spondylotic myelopathy, radiculopathy, spondylolysis / spondylolisthesis, lumbar spinal stenosis, degenerative lumbar spondylolisthesis, and degenerative lumbar scoliosis, as the binding of IL-17A to IL-17RA is associated with the symptoms. In such embodiments, the pharmaceutical product of the present invention is formulated to be suitable for delivery to cells within the intervertebral disc tissue (nucleus pulposus, transitional zone, annulus fibrosus), particularly to nucleus pulposus cells. The intervertebral disc tissue may be tissue with any degree of degeneration, aging, impairment, damage, etc. (including healthy tissue that is substantially free of degeneration, etc.), or it may be herniated tissue.

[0176] In another representative embodiment of the present invention, the pharmaceutical product of the present invention is a pharmaceutical product for treating or preventing inflammatory skin diseases such as psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, and erythrodermic psoriasis, in which the binding of IL-17A to IL-17RA is associated with the symptoms. In this embodiment, the pharmaceutical product of the present invention is formulated to be suitable for delivery to cells in skin tissue (epidermis, dermis), particularly cells (keratinocytes or corneocytes) in the basal layer, spinous layer, granular layer, and stratum corneum of the epidermis. The skin tissue may be tissue exhibiting symptoms such as erythema, infiltration / thickening, scaling, and desquamation to any degree. In addition to skin symptoms, psoriasis may also present with joint symptoms such as joint pain and deformation, and both skin and joint symptoms can be targeted for treatment or prevention.

[0177] The pharmaceutical product of the present invention can be manufactured (prepared as a pharmaceutical composition) by methods known in the pharmaceutical technology, using the IL-17A activity inhibitor or the expression inhibitor of the present invention and a pharmaceutically acceptable carrier. Examples of dosage forms of the above pharmaceutical product include parenteral formulations (e.g., liquid formulations such as injections) containing conventional adjuvants such as buffers and / or stabilizers, and topical formulations such as ointments, creams, liquids or plasters containing conventional pharmaceutical carriers.

[0178] The "subjects" to whom the pharmaceutical agent of the present invention is administered are subjects who have developed a disease in which the binding of IL-17A to IL-17RA is associated with the symptoms (for therapeutic purposes) or subjects who are at risk of developing such a disease (for preventative purposes). The "subjects" may be humans, or other mammals such as non-human primates (e.g., cynomolgus monkeys, rhesus monkeys, chimpanzees), cattle, pigs, mice, rats, and other disease model animals.

[0179] The pharmaceutical product of the present invention should be administered in an effective amount to produce the desired therapeutic or preventive effect. Such an effective amount can be appropriately adjusted by considering the dosage form, target recipient, route of administration, etc., and by determining the amount per administration, the number of administrations, and the interval between administrations (number of administrations within a certain period).

[0180] The pharmaceutical product of the present invention should be administered in an effective amount to produce the desired therapeutic or preventive effect. Such an effective amount can be appropriately adjusted by considering the dosage form, target recipient, route of administration, etc., and by determining the amount per administration, the number of administrations, and the interval between administrations (number of administrations within a certain period).

[0181] —Screening method for IL-17A activity inhibitors— The "screening method for IL-17A activity inhibitors" provided in one aspect of the present invention includes Phe60, Gln87, Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, Ser258, Cys259, Asp262, Cys263, Le The method includes evaluating the binding stability between the candidate compound and IL-17RA based on a stereomolecular model of the space surrounded by u264 and His266 and a stereomolecular model of the candidate compound, by non-covalent interactions including van der Waals forces occurring between at least 13 of the amino acid residues and atoms or groups of atoms in the candidate compound, and estimating whether the candidate compound inhibits the binding of IL-17A to IL-17RA by binding competitively with IL-17A.

[0182] The screening method for IL-17A activity inhibitors may further include a step of comparing the binding stability of candidate compounds with the binding stability of compounds (1) to (36). Such embodiments of the screening method for IL-17A activity inhibitors are preferably used, for example, to produce derivatives of compounds (1) to (36), and in particular to produce derivatives with improved IL-17A activity inhibitory activity than compounds (1) to (36).

[0183] In this specification, the matters described above regarding "IL-17A activity inhibitors" and other inventions may be applied mutatis mutandis to "binding inhibition methods."

[0184] —Methods for inhibiting binding— A “binding inhibition method” provided in one aspect of the present invention is for inhibiting the binding of IL-17A to IL-17RA and includes the step of bringing the IL-17A activity inhibitor of the present invention, as described above, into contact with IL-17RA.

[0185] Contact between IL-17A activity inhibitors and IL-17RA can be performed in vitro, ex vivo, or in vivo; in other words, both in vivo and ex vivo in humans and other animals.

[0186] In this specification, the matters described above regarding "IL-17A activity inhibitors" and other inventions may be applied mutatis mutandis to "binding inhibition methods."

[0187] —Methods for regulating expression— One aspect of the present invention provides a "method for regulating gene expression" for regulating the expression of a gene whose expression level changes upon binding of IL-17A to IL-17RA, and includes the step of bringing the IL-17A activity inhibitor of the present invention, as described above, into contact with cells expressing IL-17RA.

[0188] Contact between IL-17A activity inhibitors and IL-17RA can be performed in vitro, ex vivo, or in vivo; in other words, both in vivo and ex vivo in humans and other animals.

[0189] In this specification, the matters described above regarding "expression regulators" and other inventions may be applied mutatis mutandis to "expression regulation methods."

[0190] -Treatment method- A “treatment method” provided in one aspect of the present invention includes the step of administering the IL-17A activity inhibitor, expression regulator, or pharmaceutical of the present invention as described above to a subject who has developed or is at risk of developing a “disease in which the binding of IL-17A to IL-17RA is associated with the symptoms.”

[0191] In this specification, the matters described above with respect to "pharmaceuticals for treatment or prevention" and other inventions may be applied mutatis mutandis to "methods of treatment." [Examples]

[0192] [Reference Example 1] Immunostaining of IL-17A expressed in human intervertebral disc nucleus pulposus tissue Informed consent was obtained from the patients in accordance with the Declaration of Helsinki. Ethical review approval was obtained from the Ethics Committee of Tokai University School of Medicine. A total of 10 intervertebral disc tissue samples were excised from three patients under 16 years of age with lumbar disc herniation and three patients with idiopathic scoliosis. The level of degeneration of the excised intervertebral disc samples was evaluated according to the Pfirrmann classification using MRI. Samples excised from patients with lumbar disc herniation were degenerated (grade 3, 4, or 5), while samples excised from patients with idiopathic scoliosis were normal (grade 1 or 2).

[0193] To investigate the expression level of IL-17A in these intervertebral disc samples, immunohistochemical staining was performed using the following procedure: Samples were fixed in PBS containing 4% paraformaldehyde and embedded in paraffin. Sections were deparaffinized with xylene, rehydrated with serially diluted ethanol, and incubated overnight at 4°C with anti-IL-17A antibody (#bs-2140R, Bioss, human IL-17A specific) diluted in PBS containing 1% BSA. Subsequently, the samples were stained with a conjugate of goat anti-rabbit IgG antibody (Sigma-Aldrich) with horseradish peroxidase (HRP), and visualized by reacting with diaminobenzidine (Nacalai Tesque). Cell nuclei were stained with hematoxylin. All specimens were observed under a microscope (IX70, Olympus Corporation), and for each specimen, the total number of cells in the high-magnification field and the number of stained cells were measured, and the ratio of the latter to the former was determined.

[0194] The results are shown in Figure 37. In degenerated intervertebral disc tissue, staining with IL-17A was significantly more pronounced compared to normal intervertebral disc tissue, and a significantly higher proportion of IL-17A-expressing (IL-17A-positive) nucleus pulposus cells was confirmed.

[0195] [Reference Example 2] Effects of IL-17A stimulation on the expression levels of various genes in rat nucleus pulposus cells. Nucleus pulposus cells were isolated from 11-week-old Sprague Dawley rats according to the method of Risbud et al (Journal of Cellular Biochemistry 98, 152-159, 2006; doi:10.1002 / jcb.20765). Briefly, the intervertebral discs of the lumbar and coccyx of deeply anesthetized rats were dissected under sterile conditions, and the gel-like nucleus pulposus was separated from the annulus fibrosus (AF). After finely chopping and pipetting, the cells were cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with 20% FBS and antibiotics at 20% O2, 5% CO2, and 37°C for approximately 1-2 weeks, followed by culture in DMEM supplemented with 10% FBS and antibiotics for approximately 1-2 weeks. The resulting nucleus pulposus cells were cultured for 15 minutes to 24 hours in a hypoxic chamber (MIC-101, Billups Rothenberg Inc., USA) containing 1% O2, 5% CO2, and 94% N2.

[0196] After treating cultured rat nucleus pulposus cells with 20 or 50 ng / mL recombinant mouse IL-17A (Pepro Tech Inc., USA, #210-17) for 24 hours, the mRNA expression levels of IL-6, COX-2, mPGES1, MMP-3, and MMP-13 were quantified by real-time RT-PCR using the following procedure: Total RNA was extracted from nucleus pulposus cells using an RNAeasy mini column (Qiagen, Germany). Before elution from the column, the RNA was treated with RNase-free DNase I (Qiagen, Germany). The purified DNA-free RNA was converted to cDNA using a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, USA). Template cDNA and primers specific to each gene were added to a Power SYBR Green master mix (Applied Biosystems), and the mRNA expression levels of each gene were quantified using a Step One Plus Real-time PCR System (Applied Biosystems). Expression levels were standardized with β-actin. RT-PCR specificity and the absence of primer dimer formation were verified by analysis of the melting curve.

[0197] The results are shown in Figure 38[A]. Real-time PCR evaluation revealed a significant increase in IL-6 and COX-2, as well as a substantial increase in MMP-3, MMP-13, and mPGES1, compared to the untreated group (cont).

[0198] Rat nucleus pulposus cells, which showed the most significant increases in IL-6 and COX-2 after 24 hours of treatment with 50 ng / mL IL-17A, were quantified by Western blotting using the following procedure: Nucleus pulposus cells were placed on ice and washed with ice-cold PBS. To prepare total cell protein, cells were lysed with a lysis buffer containing 10 mM Tris-HCl (pH 7.6), 50 mM NaCl, 5 mM EDTA, 1% Nonidet P-40, a complete protease inhibitor cocktail (Roche, USA), 1 mM NaF, and 1 mM Na3VO4. Proteins were fractionated by SDS-PAGE and transferred to Immobilon-P polyvinylidene difluoride membrane (Millipore, USA). The membrane was blocked with blocking buffer (PBS dissolved with 5% BSA and 0.1% NaN3), and then incubated overnight at 4°C with either an anti-IL-6 antibody (#bs-0782R, Bios), an anti-COX-2 antibody (#NB100-689SS, Novus), or an anti-β-actin antibody (#A2228, Sigma-Aldrich). Each antibody was diluted with Can Get Signal Immunoreaction Enhancer Solution (Toyobo Co., Ltd., Japan). The chemiluminescence signal was visualized using Immobilion Western Chemilunescent HRP Substrate (Millipore) and scanned using the Ez-Capture MG imaging system (ATTO, Japan). Western blotting data were quantified by density scanning of the film using the Macintosh computer software "CS Analyzer" (ATTO, Japan). In this process, the concentration of each gene band was standardized by the concentration of the β-actin band as a control.

[0199] The results are shown in Figure 38[B]. When rat nucleus pulposus cells were administered 50 ng / ml recombinant mouse IL-17A and treated for 24 hours, the expression levels of COX-2 and IL-6 as proteins were significantly increased.

[0200] Furthermore, the transcriptional activity of COX-2 in rat nucleus pulposus cells treated with 50 ng / mL recombinant mouse IL-17A for 24 hours was measured using a promoter assay method following the procedure below. 24 hours prior to transfection, rat nucleus pulposus cells were plated in a 96-well plate (8 × 10⁶). 3 Cells were transferred to a well. The cells were transfected with either phPES2-1432 / +59 (a plasmid containing the COX-2 promoter and luciferase construct, kindly provided by Dr. Akihiko Hiyama of Tokai University, (Hiyama A., et al., Journal of orthopaedic research 33, 1756-1768, 2015; doi:10.1002 / jor.22959) or pGL4.74 (Promega, USA), a backbone plasmid containing only the Renilla reniformis luciferase gene as an internal control. Lipofectamine 2000 (Invitrogen, USA) was used as the transfection reagent. After 24 hours of culture under hypoxic conditions, reporter activity was measured. Dual-Luciferase Reporter The activity of firefly luciferase and sea urchin luciferase was measured using an Assay system (Promega) and a luminometer (TD-20 / 20, Turner Designs, USA).

[0201] The results are shown in Figure 38[C]. Treatment of rat nucleus pulposus cells with 50 ng / ml recombinant mouse IL-17A for 24 hours significantly increased COX-2 transcriptional activity.

[0202] [Reference Example 3] Reaction to inhibition of IL-17A activity by an anti-IL-17A neutralizing antibody Except for the modification of including a group that received a solution prepared by mixing 50 ng / ml recombinant mouse IL-17A with 0.5 μg / ml anti-IL-17A antibody (#DDX0336P-50, Novus, specific to human and mouse IL-17A) as a neutralizing antibody and reacting them for 1 hour, the procedure was the same as in [Reference Example 2], and the mRNA expression levels of IL-6, COX-2, mPGES1, MMP-3, and MMP-13 were quantified, the protein expression levels of IL-6 and COX-2 were quantified, and the transcriptional activity of COX-2 was measured.

[0203] The results are shown in Figures 39[A], [B], and [C], respectively. From [A], it can be seen that the expression levels of mRNA for IL-6, COX-2, mPGES1, MMP-3, and MMP-13 were all significantly lower in the group receiving anti-IL-17A neutralizing antibody compared to the group receiving IL-17A alone ("IL-17A" is "+", "anti-IL-17A" is "-"). From [B], it can be seen that the expression levels of IL-6 and COX-2 proteins were similarly significantly lower in the group receiving anti-IL-17A neutralizing antibody compared to the group receiving IL-17A alone. From [C], it can be seen that the transcriptional activity of COX-2 was similarly significantly lower in the group receiving anti-IL-17A neutralizing antibody compared to the group receiving IL-17A alone. These results confirm that the anti-IL-17A neutralizing antibody inhibits the uplifting effect of IL-17A on the expression levels of the above genes.

[0204] [Reference Example 4] Effects of IL-6 stimulation on the expression levels of various genes in rat nucleus pulposus (NP) cells. We analyzed IL-6, whose mRNA expression level was significantly increased by IL-17A, and evaluated the effects of IL-6 on rat NP cells. Rat NP cells were administered IL-6 at a dose of 50 ng / ml and cultured for 24 hours under 1% oxygen conditions. Then, the mRNA expression levels of COX-2, IL-17A, MMP-3, and MP-13 were quantified by real-time RT-PCR using the same procedure as in [Reference Example 2]. Furthermore, the protein expression level of COX-2 and the transcriptional activity of COX-2 were also evaluated using the same procedure as in [Reference Example 2].

[0205] The results are shown in Figures 40[A], [B], and [C], respectively. From [A], the IL-6-administered group showed a significant increase in the expression levels of COX-2, MMP-3, and MMP-13 mRNA compared to the untreated group, but no significant change was observed in the expression level of IL-17A mRNA. From [B], the IL-6-administered group also showed a significant increase in the expression level of COX-2 protein compared to the untreated group. From [C], the IL-6-administered group also showed a significant improvement in COX-2 transcriptional activity compared to the untreated group.

[0206] [Example 1] Evaluation of the compound of the present invention as an IL-17A activity inhibitor in rat nucleus pulposus (NP) cells. The procedure is the same as in [Reference Example 2], except that a group is given a solution prepared by mixing 50 ng / ml recombinant mouse IL-17A with 50 μg / ml of one of the following compounds: (3) (STK630921), (2) (PB203263256), (5) (Z9215), or (11) (P2000N-53454). In other words, the anti-IL-17 solution is administered at a concentration of 0.5 μg / ml. Except for changing the use of one of the compounds (3), (2), (5), or (11) at a concentration of 50 μg / ml instead of antibody A, the procedure was the same as in the "anti-IL-17A neutralizing antibody combination group" in [Reference Example 3], in which (A) the expression levels of mRNA of IL-6, COX-2, mPGES1, MMP-3, and MMP-13 were quantified, (B) the expression levels of proteins of IL-6 and COX-2 were quantified, and (C) the transcriptional activity of COX-2 was measured. In (B) and (C), only compound (3), which was considered to be the most effective against IL-6 and COX-2 among the compounds of the present invention as described in (A) below, was used.

[0207] The results are shown in Figures 41[A], [B], and [C], respectively. From [A], it can be seen that the expression levels of mRNA for IL-6, COX-2, mPGES1, MMP-3, and MMP-13 were significantly lower in the group treated with IL-17A in combination with the compounds (3), (2), (5), or (11) of the present invention compared to the group treated with IL-17A alone. In particular, compound (3) showed a significant decrease in the expression levels of mRNA for IL-6 and COX-2. From [B], it can be seen that the protein expression levels of IL-6 and COX-2 were significantly lower in the IL-17+STK group than in the IL-17 group. From [C], it can be seen that the transcriptional activity of COX-2 was similarly significantly lower in the IL-17+STK group than in the IL-17 group. From these results, it has been confirmed that the compounds of the present invention, like anti-IL-17A neutralizing antibodies, have the effect of inhibiting the upregulation effect of IL-17A on the expression levels of the above-mentioned genes.

[0208] Furthermore, when compound (9)(F3382) was used as a compound of the present invention and the expression level of IL-6 mRNA was quantified in the same manner as above, the expression level was significantly reduced in the group treated with IL-17A and compound (9) in combination compared to the group treated with IL-17A alone (*p<0.05, not shown), confirming that compound (11), like the other compounds of the present invention, has the effect of inhibiting the uplift effect of IL-17A on the expression levels of the above-mentioned genes.

[0209] [Example 2] Evaluation of the compound of the present invention as an IL-17A activity inhibitor in human nucleus pulposus (NP) cells Except for changing the sample from rat NP cells to human NP cells (obtained in [Reference Example 1]) and using compound 1 (STK) as the compound of the present invention at two concentrations, 50 μg / ml and 100 μg / ml, the expression levels of IL-6 and COX-2 mRNA were quantified using the same procedure as in [Example 1].

[0210] The results are shown in Figure 42. IL-6 mRNA expression in human NP cells showed a decreasing trend after 24-hour administration of STK 50 μg / ml, and STK 100 μg / ml administration showed a significant decrease compared to the IL-17A monotherapy group. COX-2 mRNA expression did not show a clear inhibitory effect 24 hours after STK 50 μg / ml or 100 μg / ml administration, but a significant decrease was observed 36 hours after 50 μg / ml administration.

[0211] [Example 3] Verification of the effects of IL-17A and the compound of the present invention on the MAPK pathway IL-17A has been reported to be involved in COX-2 expression via the MAPK pathway. The involvement of MAPK factors (p38, JNK, and ERK) in IL-17A, COX-2, and IL-6 expression, and the effects of compound (1) of the present invention on these MAPK factors were evaluated using the following method.

[0212] Rat NP cells were cultured for 24 hours under 1% oxygen conditions, either with 50 ng / ml of recombinant mouse IL-17A, along with 10 μM concentrations of the p38 phosphorylation inhibitor "SB203580," the JNK phosphorylation inhibitor "SP600125," or the ERK phosphorylation inhibitor "PD98059," respectively, or without administration of these inhibitors. The expression levels of COX-2 and IL-6 mRNA were then quantified by real-time RT-PCR using the same procedure as in [Reference Example 2].

[0213] The results are shown in Figures 43[A] and [B]. Significant suppression of COX-2 mRNA expression was observed in each of the SB, SP, and PD treatment groups, as well as significant suppression of IL-6 mRNA expression in each of the SB and PD treatment groups. These results suggest that activation of p38, JNK, and ERK may be involved in COX-2 expression by IL-17A, and activation of p38 and ERK may be involved in IL-6 expression.

[0214] Next, rat NP cells were administered 50 μg / ml of compound (1) along with 50 ng / ml of IL-17A, or without administration, and cultured for 15 or 30 minutes under 1% oxygen conditions. Then, the expression levels of phosphorylated p38, p38, phosphorylated JNK, JNK, phosphorylated ERK, and ERK proteins were quantified by Western blotting using the same procedure as in [Reference Example 2].

[0215] The results are shown in Figures 43[C], [D], [E], and [F]. Phosphorylation of p38 decreased from 15 minutes after administration of compound (1) (C, E), and a significant decrease was observed 30 minutes after administration compared to the IL-17A monotherapy group (D, F). Therefore, it was suggested that IL-17A promotes the phosphorylation (activation) of p38 and ERK in the MAPK pathway, and that administration of compound (1) at least suppresses the activation of p38 by IL-17A, and as a result, may be involved in the suppression of COX-2 and IL-6 expression.

[0216] [Comparative Example 1] The COX-2 mRNA expression level was quantified using the same procedure as in [Reference Example 2], except that a group (synd group) was administered a solution prepared by mixing 50 ng / ml recombinant mouse IL-17A with 50 μg / ml of the compound from Non-Patent Document 3 (Liu et al., Science Signaling 2017) and reacting it for 1 hour. The COX-2 mRNA expression level of the synd group was compared with that of the IL-17+STK group obtained in [Example 1].

[0217] The results are shown in Figures 44[A] and [B]. The compound in Non-Patent Literature 3 did not inhibit IL-17A activity and reduce COX-2 mRNA expression in rat NP cells, demonstrating that compound (1) of the present invention is superior in this regard.

[0218] [Example 4] Confirmation of the therapeutic effect of a pharmaceutical product containing the compound of the present invention using a mouse psoriasis skin model. The backs of 10-week-old male BJ6J mice were shaved to a depth of approximately 1 x 1.5 cm, and imiquimod (IMQ, a drug that causes psoriasis-like dermatitis in mice) cream was applied daily from day 1 to day 4. From day 5, 6-8 hours after the initial application of IMQ cream, a DMSO solution containing 1 mg of compound (3) (database registration name: STK630921) was applied (STK group = compound (3) treatment group). Similar applications of IMQ cream and compound (3) solution were performed daily from day 6 to day 9. As control groups, we established the following: a group (Sham group) that received IMQ cream and an equal amount of DMSO (the solvent for a DMSO solution containing 1 mg of compound (3) from day 5 to day 9; a group (IMQ group) that received only IMQ cream from day 5 to day 9; and a group (Normal group) that received no initial application of IMQ cream or any treatment from day 5 to day 9. Each group consisted of three mice.

[0219] On day 10, skin samples were collected from mice in the STK, Sham, IMQ, and normal groups. One sample was prepared from each mouse, stained with hematoxylin eosin (HE) and another with immunofluorescence staining using anti-CXCL1 antibody. For the HE-stained samples, the thickness of the epidermal layer was measured at two or more locations within the same magnification field of view for each sample, and the mean values ​​were statistically analyzed (significant difference found: p<0.05, n=3). For the immunofluorescence stained samples, the area exhibiting a fluorescence intensity above a certain value (i.e., positive CXCL1 expression) within a specified area of ​​the same size was measured using the image analysis software "Image J" (NIH: National Institutes of Health) and statistically analyzed (significant difference found: p<0.05, n=3).

[0220] The results regarding epidermal thickness and CXCL1 expression are shown in Figures 47 and 48, respectively. In the STK group (compound (3) treatment group), there was a significant decrease in the thickness of the epidermal layer, which exhibits abnormal thickening, a typical pathological condition of psoriasis (p<0.001), and a significant decrease in the expression of CXCL1, one of the factors that induce inflammation in the epidermis in psoriasis (p<0.05), indicating a therapeutic effect against psoriasis.

[0221] [Example 5] Confirmation of the therapeutic effect of a pharmaceutical product containing the compound of the present invention using a rat intervertebral disc degeneration model. In 11-week-old male SD rats (body weight 300-350g), a 23G needle was inserted approximately 5mm into the caudal intervertebral disc, rotated 360°, and left in place for 30 seconds to induce intervertebral disc degeneration (day 0). Fourteen days after the onset of intervertebral disc degeneration (day 14), 10 μL of DMSO solution containing 1 mg of compound (3) (database registration name: STK630921) was injected into the degenerated intervertebral disc (STK group = compound (3) treatment group). As control groups, the Sham group received the same amount of DMSO only instead of 10 μL of DMSO solution containing 1 mg of compound (3), the degenerated group received no treatment after intervertebral disc degeneration, and the normal group received no treatment or intervertebral disc degeneration.

[0222] Twenty-eight days after intervertebral disc degeneration (day 28), caudal vertebrae were collected from rats in the STK group, Sham group, degenerative group, and normal group. After fixation with 4% PFA, decalcification was performed, and specimen sections were prepared. Each specimen section was immunostained using an anti-IL-6 antibody. For each immunostained specimen, the number of IL-6-positive cells was measured in 3-4 arbitrarily selected spots of the same area within the intervertebral disc tissue at the same magnification field, and the IL-6-positive cell expression rate relative to the total number of cells in each spot was calculated.

[0223] The results are shown in Figure 49. In the STK group (compound (3) treatment group), a significant decrease in the expression rate of IL-6-positive cells (p<0.05) was observed, indicating a therapeutic effect against intervertebral disc degeneration.

Claims

1. An IL-17A activity inhibitor that inhibits the binding of IL-17A to IL-17RA, comprising a compound represented by the following structural formulas (1) to (3), (5), (9), or (11) (hereinafter referred to as "compounds (1) to (3), (5), (9), or (11)," respectively), or a pharmaceutically acceptable salt or solvate thereof. Table 1

2. A pharmaceutical product for the treatment or prevention of a disease in which the binding of IL-17A to IL-17RA is associated with the symptoms, comprising the IL-17A activity inhibitor described in claim 1 as an active ingredient, The aforementioned binding of IL-17A to IL-17RA is associated with the following conditions: lumbar or cervical disc disease, herniated disc, cervical spondylotic myelopathy, radiculopathy, spondylolysis / spondylolisthesis, lumbar spinal stenosis, degenerative spondylolisthesis, degenerative scoliosis, inflammatory skin diseases, inflammatory joint diseases, inflammatory bowel disease, autoimmune diseases, organ / tissue transplant rejection, or sepsis.

3. The extracellular domains of human IL-17RA include Phe60, Gln87, Asp121, Pro122, Asp123, Gln124, Asp153, Cys154, Glu155, Lys160, Pro164, Cys165, Ser167, Ser168, Gly169, Ser170, Leu171, Trp172, Asp173, Pro174, Pro254, Phe256, and Ser258. From the three-dimensional molecular model of the space surrounded by Cys259, Asp262, Cys263, Leu264, and His266, or the three-dimensional molecular model of the space surrounded by amino acid residues corresponding to the 28 amino acid residues contained in the extracellular domain of IL-17RA of non-human animals (provided that the homology of these amino acid residues is 80% or more), and the three-dimensional molecular model of the candidate compound, The binding stability between the candidate compound and IL-17RA is evaluated by non-covalent interactions, including van der Waals forces, that occur between at least 13 atoms or groups of atoms among the amino acid residues and atoms or groups of atoms in the candidate compound. The candidate compound competitively binds to IL-17RA, thereby transferring IL-17A to IL-17RA. A screening method for IL-17A activity inhibitors, comprising a step of estimating whether or not they have an effect of inhibiting binding.

4. The screening method according to claim 3, further comprising the step of comparing the binding stability of the candidate compound with the binding stability of compounds (1) to (3), (5), (9) and / or (11) described in claim 1.

5. A method for inhibiting the binding of IL-17A to IL-17RA, comprising the step of contacting IL-17RA with the IL-17A activity inhibitor described in claim 1 in vitro in humans and other animals.

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