90 results about "Homosteroids" patented technology

This invention relates to novel compounds of the Formula (I), (I*), (I**), I, Ia, Ib, Ic, Id, Ie, If, Ig, Il^1-3, Im^1-3, In^1-3, or Io^1-2, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

Novel pentacyclic steroids and pentacyclic D-homosteroids comprising: (i) the tetracyclic steroid ring system or tetracyclic D-homosteroid ring system, respectively; (ii) a C(3) substituent selected from the group consisting of (a) a hydroxyl or carboxyl in the α-configuration and (b) a sulfate or other negatively charged moiety; and (iii) a fused fifth ring, the fused fifth ring comprising a hydrogen bond acceptor, and (a) in the case of the pentacyclic steroid the C(13) and C(17) carbons, or (b) in the case of the pentacyclic D-homosteroid the C(13) and C(17a) carbons, having utility as anesthetics and in the treatment of disorders relating to GABA function and activity.

A compound having Formula I

R₁-Z-R₂  Formula I

wherein R₁ is an optionally substituted phenyl ring; R₂ is or comprises an optionally substituted-aromatic ring; and Z is -X-Y-L- or -Y-X-L- wherein either X is selected from —S(═O)(═O)— and —C(═O)—, and Y is —NR₃—; or X is selected from —S(═O)(═O)— and —S—, and Y is —C(R₄)(R₅)—; L is an optional linker; and R₃, R₄ and R₅ are each independently selected from H and hydrocarbyl; and wherein when R₂ comprises the following structural moiety

wherein Q is an atom selected from the group consisting of S, O, N and C; the compound is selected from compounds of the formulae R₁C(═O)—NR₃-L-R₂; R₁—S(═O)(═O)—C(R₄)(R₅)-L-R₂; R₁—S—C(R₄)(R₅)-L-R₂; R₁—NR₃—S(═O)(═O)-L-R₂; R₁—NR₃—C(═O)-L-R₂; R₁—C(R₄)(R₅)—S(═O)(═O)-L-R₂; and R₁—C(R₄)(R₅)—S-L-R₂.

The invention relates to hydroxysteroid dehydrogenase and particularly relates to a clostridium sardiniense 7alpha-hydroxysteroid dehydrogenase mutant T145S. The amino acid sequence of the clostridium sardiniense 7alpha-hydroxysteroid dehydrogenase mutant T145S is shown by SEQ ID No:2 and obtained by changing the 145th-site amino acid of the 7alpha-hydroxysteroid dehydrogenase with an amino acid sequence of SEQ ID No:1 from Thr into Ser. The mutant is 4.85 times of a wild type in the catalysis efficiency against the substrates TCDCA and NADP<+> and has a huge application potential in a biotransformation process of CDCA/TCDCA for obtaining UDCA/TUDCA.

The invention relates to hydroxysteroid dehydrogenase, and in particular to 7alpha-hydroxysteroid dehydrogenase (St-2-2) mutants. The amino acid sequences of the mutants are shown as SEQ ID NO:2, 3, 4, 5, 6, 7, 8, 9 or 10, and are obtained by changing the 255th amino acid of the 7alpha-hydroxysteroid dehydrogenase with an amino acid sequence of SEQ ID NO:1 from Ile to Tyr, Gln, Leu, Thr, Gly, Asn,Ser, Ala or Phe. In the presence of same substrates TCDCA and NADP<+>, enzyme activity of the mutants is respectively 1.49, 1.78, 1.79, 1.79, 1.93, 2.44, 2.58, 2.97 and 3.34 times of enzyme activityof a wild type hydroxysteroid dehydrogenase, and the mutant has a great application potential in a process of obtaining tauroursodeoxycholic acid (TUDCA) through biotransformation of taurochenodeoxycholic acid (TCDCA).

The invention relates to HSDH (hydroxysteroid dehydrogenase), in particular to a gene S1-a-1 of novel 7 alpha-HSDH. A nucleotide sequence of the gene is shown as SEQ ID NO.2, the novel 7 alpha-HSDH is encoded, a nucleotide sequence of the novel 7 alpha-HSDH is shown as SEQ ID NO.1, the novel 7 alpha-HSDH can be used for catalyzing CDCA (chenodeoxycholic acid) and TCDCA (taurochenodeoxycholic acid) to generate 7K-LCA (7-ketone lithocholic acid) and T7K-LCA (taurine-7-ketone lithocholic acid), wherein the catalytic activity of the novel 7 alpha-HSDH for CDCA is about 5 times of that of 7 alpha-HSDH of Sardinia clostridium, and the catalytic activity of the novel 7 alpha-HSDH for TCDCA is about over 2.5 times of that of 7 alpha-HSDH of Sardinia clostridium, therefore, the novel 7 alpha-HSDH has a great industrial application value.

The invention discloses the therapeutic and prophylactic administration of leptin to (i) an infant of low birth weight for age; (ii) a nursing mother of an infant, the infant having low birth weight for age; or (iii) a pregnant female predisposed to giving birth to an infant of low birth weight for age; for the prevention or treatment, in later life of the infant, of a metabolic disorder or other condition associated with low birth weight, such as type 2 diabetes, obesity, cardiovascular disease, gestational diabetes, impaired glucose tolerance, insulin resistance, hypertension or syndrome X. It is thought that the beneficial properties of leptin may be due at least in part to an effect on glucocorticoid metabolism, in particular to an increase in type 2 11β-hydroxysteroid dehydrogenase activity.

The present invention relates to a coupled biotransformation process of converting chenodeoxycholic acid (CDCA) and related compounds to ursodeoxycholic acid (UDCA) and related compounds. It also relates to the cloning, expression, and biochemical characterization of a novel NADP⁺-dependent 7α-hydroxysteroid dehydrogenase (7α-HSDH) from Clostridium difficile, cofactor switch mutants thereof, and their application for the oxidation of bile acids. A further aspect of the invention relates to novel NADP-dependent cofactor switch mutants of the NADP⁺-dependent 7α-HSDH of E. coli and their application for the oxidation of bile acids.

The invention relates to hydroxysteroid dehydrogenase (HSDH), in particular to a 7[alpha]-HSDH mutant St-2-2 [delta]C10 and application thereof. The amino acid sequence of the 7[alpha]-HSDH mutant isshown as SEQ ID NO: 2, and the 7[alpha]-HSDH mutant is obtained by truncating 10 amino acids at the C end of 7[alpha]-HSDH with the amino acid sequence shown as SEQ ID NO: 1. The mutant has substrateselectivity, can specifically catalyze CDCA and taurine or glycine conjugates thereof, has no catalytic activity on CA and taurine or glycine conjugates thereof, can be used for efficiently synthesizing TUDCA from complex substrate chicken gall powder, does not generate toxic substances, namely by-product TUCA, and has huge application potential in the process of obtaining the TUDCA through specific biotransformation of the TCDCA.

There is provided a compound having Formula I

wherein

• each of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are independently selected from
• (a) H, (b) R₁₃, —OC(R₁₃)₃, —OCH(R₁₃)₂, —OCH₂R₁₃, C(R₁₃)₃, —CH(R₁₃)₂, or —CH₂R₁₃ wherein R₁₃ is a halogen; (c) —CN; (d) optionally substituted alkyl, (e) optionally substituted heteroalkyl; (f) optionally substituted aryl; (g) optionally substituted heteroaryl; (h) optionally substituted arylalkyl; (i) optionally substituted heteroarylalkyl; (j) hydroxy; (k) alkoxy; (l) aryloxy; (m) —SO₂-alkyl; and (n) —N(R₁₄)C(O)R₁₅,
• wherein R₁₄ and R₁₅ are independently selected from H and hydrocarbyl,
• wherein the optional substituents of (d) (e) (f) (h) and (i) are selected from the group consisting of: C_1-6 alkyl, halo, cyano, nitro, haloalkyl, hydroxy, C_1-6 alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl;
• wherein n and p are independently selected from 0 and 1;
• X is an optional group selected from O, S, S=0, S(═O)₂, C═O, S(═O)₂NR₁₆, C═ONR₁₇, NR₁₈, in which R₁₆, R₁₇, and R₁₈ are independently selected from H and hydrocarbyl,
• R₁₀ is selected from H and hydrocarbyl,
• R₁₁ is selected from CR₁₉R₂₀ and C═O, in which R₁₉ and R₂₀ are independently selected from H and hydrocarbyl,
• R₁₂ is selected from a substituted five or six membered carbon rings optionally containing one or more hetero atoms selected from N, S, and O and optionally having fused thereto a further ring, and wherein the one or more substituents are selected from hydrocarbyl groups.

The invention discloses a DNA sequence of a polypeptide chain with 3 alpha-HSD (3 alpha-hydroxysteroid dehydrogenase) activity. The DNA sequence comprises a complementary chain sequence. The DNA sequence is characterized in that an expression product of the DNA sequence has 3 alpha-hydroxysteroid dehydrogenase activity and is a novel Pseudomonas aeruginosa 3 alpha-hydroxysteroid dehydrogenase. The DNA sequence comprises the following contents: a pseudomonas aeruginosa 3 alpha-hydroxysteriod dehydrogenase gene sequence obtained by utilizing bioinformatics analysis, a recombinant expression vector which contains the pseudomonas aeruginosa 3 alpha-hydroxysteroid dehydrogenase gene sequence, a genetically engineered bacterium which expresses the 3 alpha-hydroxysteroid dehydrogenase 3-hsdA and an enzyme kinetics parameter of the 3 alpha-hydroxysteroid dehydrogenase.

The disclosure provides an injectable neurosteroid nanoparticle formulation comprising nanoparticles having a D50 of less than 2000 nm the nanoparticles comprising a neurosteroid of Formula I, where the variables R1-R9 and X are defined herein and at least one surface stabilizer. The surface stabilizer can be a polymeric surface stabilizer such as hydroxyethyl starch, dextran, or povidone. The injectable neurosteroid nanoparticle formulation can be an intravenous formulation. The disclosure also provides a lyophilized powder of the injectable neurosteroid nanoparticle formulation that can be reconstituted in an aqueous solution prior to administration. The disclosure provides injectable neurosteroid nanoparticle formulations and dry powders of such formulations that have been sterilized byebeam irradiation. The disclosure provides a method of treating a patient having a seizure disorder, stroke, or traumatic brain injury, comprising administering an effective amount of the injectableneurosteroid nanoparticle formulation. The disclosure also provides combination methods in which the injectable neurosteroid nanoparticle formulation is a first active agent that is administered in combination with at least one additional active agent.

Novel compounds are provided which are 1 1-beta-hydroxysteroid dehydrogenase type I inhibitors. 1 1-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 1 1-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure: W-L-Z or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein W, L are defined herein and Z is selected from the following bicyclic heteroaryl groups: (a), (b), (c), (d).

The invention relates to hydroxysteroid dehydrogenase, in particular to a new 7alpha-hydroxysteroid dehydrogenase gene Y1-a-1. The nucleotide sequence of the gene is as shown in SEQ ID NO. 2. New 7alpha-hydroxysteroid dehydrogenase is coded, and the amino acid sequence of new 7alpha-hydroxysteroid dehydrogenase is as shown in SEQ ID NO.1; new 7alpha-hydroxysteroid dehydrogenase can catalyze chenodeoxycholic acid (CDCA) and taurochenodeoxycholic acid (TCDCA) to generate 7-ketone lithocholic acid (7K-LCA) and tauro 7-ketone lithocholic acid (T7K-LCA); the catalysis activity for CDCA or TCDCA is more than two times that of existing Sardinia clostridium 7alpha-HSDH, and the new 7alpha-hydroxysteroid dehydrogenase gene Y1-a-1 has an extremely large industrial application value.

The invention relates to a 7[beta]-hydroxysteroid dehydrogenase mutant and application thereof in preparation of UDCA, and belongs to the technical field of enzyme engineering. An amino acid sequenceshown in SEQ ID NO: 2 is obtained through mutant library construction and a high-throughput screening method. Key amino acids influencing the activity of 7[beta]-HSDH are determined through error-prone PCR, site-specific saturation mutagenesis is carried out, 200 mmol/L 7-KLCA99% can be converted into UDCA through the screened 7[beta] hydroxysteroid dehydrogenase mutant SEQ ID NO: 2, and the industrial production requirement is basically met.

There is provided a compound having Formula (I) R₁-Z-R₂ wherein R₁ is a group selected from optionally substituted fused polycyclic groups, substituted alkyl groups, branched alkyl groups, and optionally substituted cycloalkyl groups Z is a linker which is or comprises a carbonyl group or a isostere of a carbonyl group R₂ is selected from optionally substituted aromatic rings and optionally substituted heterocyclic rings wherein (a) R₂ is a 2-substituted thiophene group, and/or (b) Z is a group of the formula —C(═O)—CR₃R₄—X—(CR₅R₆)n-, wherein X is selected from NR₇, S, O, S═O, and S(═O)₂, wherein n is 0 or 1 and/or (c) R₁ is an adamantyl group and Z is or comprises an amide group, and/or (d) R₁ is an adamantyl group and Z is or comprises a group of the formula —(CR₈R₉)p-NR₁₀—S(═O)₂—(CR₁₁R₁₂)q-, wherein p is 0 or 1 and q is 0 or 1 and/or (e) R₁ is an adamantyl group and Z is or comprises a group of the formula —(CR₁₃R₁₄)V—Y—(CR₁₅R₁₆)W— where Y is a heteroaryl group in which a bond in the heteroaryl ring is a isostere of a carbonyl group, wherein v is o or 1 and w is 0 or 1; wherein each of R₃, R₄, R₅, R₆, R₈, R₉, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆, are independently selected from H, hydrocarbyl and halogen, wherein each of R₇ and R₁₀ are independently selected from H and hydrocarbyl.