Fatty acid-D-amino acid peptide complex as an anaplerotic compound for use in the treatment of plasma propionate, methylmalonic aciduria, and energy metabolism disorders

Abstract

Provided herein is a method of providing an anaplerotic compound to a patient in need thereof. This method can be used to treat a patient's propionic academia, methylmalonic academia, or fatty acid oxidation disorder. Also provided herein are compounds useful in these methods, and these compounds comprise an adipic acid or methylmalonic acid moiety linked to 1 to 3 amino acids, such as D-amino acids, for example, D-Ser, D-His, D-Lys, D-Leu, and / or D-Ala.

Description

[Technical Field]

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 394,136, filed August 1, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Statement regarding federal government funding assistance This invention was made with government support under Grant Nos. DK054936 and DK109907-05A1 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Provided herein are methods for treating propionic acidemia and methylmalonic aciduria, glutaric acidemia I and glutaric acidemia II, and fatty acid oxidation disorders. Also provided herein are compounds, compositions of matter specifically designed to treat propionic acidemia and methylmalonic aciduria and fatty acid oxidation disorders.

[0004] Pathologies resulting from a deficiency of succinyl-CoA include propionic academia (PA) (OMIM 606054); congenital metabolic disorders that cause methylmalonic academia are described in relation to OMIM 21000 (Beaumont syndrome), OMIM 609058 (methylmalonyl-CoA mutase), OMIM 613646 (transient methylmalonic academia due to transcobalamin receptor deficiency), OMIM 251100 (cblA type methylmalonic academia), and OMIM 251110 (cblB type methylmalonic academia); glutaric academia I (GA1) OMIM 231670 and glutaric academia II or glutaric aciduria II (GA2) OMIM 231680; and fatty acid oxidation disorders include medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (OMIM 201450); very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM 201475); trifunctional protein (TFP) deficiency (OMIM 609015); long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (OMIM 609016); and carnitine palmitoyltransferase II (CPT II) deficiency (OMIM 600649). Also included are disorders that cause mitochondrial dysfunction resulting in a decrease in mitochondrial ATP production.

[0005] Anaplerosis refers to the replenishment of catalytic intermediates in the circuit that transports acetyl-CoA when it is oxidized. Major anaplerotic cellular substrates include pyruvate, glutamine / glutamic acid, aspartic acid / asparagine, and precursors of propionyl-CoA (odd-chain fatty acids, certain amino acids, C(5)-keto bodies). Compounds, compositions, and therapeutic methods useful for replenishing deficiencies of TCA cycle intermediates such as succinyl-CoA deficiency are desirable. Summary of the Invention

[0006] Summary In this specification, according to one aspect or embodiment, a method of providing an anaplerotic compound to a patient in need thereof, comprising administering to the patient a compound having the structure A-B or B-A', wherein in the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or a linear or branched fatty acid moiety selected from adipic acid, 3-hydroxy-adipic acid, 3-keto adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, linear fatty acids, or branched fatty acids; A' comprises a linear or branched fatty acid moiety selected from 6-hydroxy-hexanoic acid (hydroxyl linked to B carboxylic acid as an ester bond), 6-amino-hexanoic acid (linked to B carboxylic acid via an amide bond), or 6-amino-2,4-dimethylheptanoic acid (linked to B carboxylic acid via an amide bond); B comprises at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val, a D-dipeptide of D-amino acids, or a D-tripeptide, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or linked to A' by an ester bond or an amide bond, or a pharmaceutically acceptable salt thereof is provided.

[0007] Also, in this specification, according to one aspect or embodiment, a method of treating a patient having propionic academia (PA), methylmalonic academia (MMA), or fatty acid oxidation disorder and having an abnormally low amount of anaplerotic intermediates, comprising administering to the patient the structure A-B or B-A': a. A compound having the formula: [For treating PA, in the structure, A is a dicarboxylic acid, tricarboxylic acid, or even-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid; A' is an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid; B is at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or to A' by an amide bond or an ester bond, and is a D-amino acid, D-dipeptide of D-amino acids, or D-tripeptide], or a pharmaceutically acceptable salt thereof; b. A compound having the formula: [For treating MMA, in the structure, A is a dicarboxylic acid, tricarboxylic acid, or even-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, citric acid, isocitric acid, oxaloacetic acid, and α-ketoglutaric acid; A' is an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid or 6-amino-hexanoic acid; B is at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or to A' by an amide bond or an ester bond, and is a D-amino acid, D-dipeptide of D-amino acids, or D-tripeptide], or a pharmaceutically acceptable salt thereof; or c. When treating fatty acid oxidation disorders, in the structure, A is a dicarboxylic acid, tricarboxylic acid, or an even-chain or branched-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, even-chain fatty acids, or branched-chain fatty acids; A' is an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid, or 6-amino-2,4-dimethylheptanoic acid; B is at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Thr, D-Ile, D-Val, D-Asp, D-Asn, or D-Leu, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or to A' by an amide bond or an ester bond, and comprises a D-amino acid, a D-dipeptide of a D-amino acid, or a D-tripeptide), or a pharmaceutically acceptable salt thereof A method comprising administering the same is also provided.

[0008] Also, according to a further aspect or embodiment, herein, structure A-B or B-A’ [in the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or a straight-chain or branched-chain fatty acid moiety selected from adipic acid, 3-hydroxy-adipic acid, 3-keto adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, straight-chain fatty acid, or branched-chain fatty acid; A’ comprises a straight-chain or branched-chain fatty acid moiety selected from 6-hydroxy-hexanoic acid (hydroxyl linked to B carboxylic acid as an ester bond), 6-amino-hexanoic acid (linked to B carboxylic acid via an amide bond), or 6-amino-2,4-dimethylheptanoic acid (linked to B carboxylic acid via an amide bond); B is an amino acid, D-dipeptide, or D-tripeptide comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or to A’ by an ester bond or an amide bond]. A compound having the same, or a pharmaceutically acceptable salt thereof, is also provided.

[0009] The following numbered items outline various aspects or embodiments of the present invention: A method of providing an anaplerotic compound to a patient in need thereof, comprising administering to said patient a compound having the structure A-B or B-A' [wherein in the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or a linear or branched fatty acid moiety selected from adipic acid, 3-hydroxy-adipic acid, 3-ketoadipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, linear fatty acids, or branched fatty acids; A' comprises a linear or branched fatty acid moiety selected from 6-hydroxy-hexanoic acid (hydroxyl linked to B carboxylic acid as an ester bond), 6-amino-hexanoic acid (linked to B carboxylic acid via an amide bond), or 6-amino-2,4-dimethylheptanoic acid (linked to B carboxylic acid via an amide bond); B comprises at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val, a D-dipeptide of D-amino acids, or a D-tripeptide, which is linked to A by an amide bond, or in the case of D-Ser by an amide bond or an ester bond, or to A' by an ester bond or an amide bond], or a pharmaceutically acceptable salt thereof.

[0010] The method according to claim 1 for the treatment of fatty acid oxidation disorders, wherein said compound has the structure A-B [wherein in the structure, A comprises an adipic acid moiety or a methylmalonic acid moiety; B comprises 1 to 3 D-amino acids selected from D-Ser, D-Ala, D-Lys, D-Leu, or D-His, which are linked to A by an amide bond, or in the case of D-Ser by an amide bond or an ester bond], or a pharmaceutically acceptable salt thereof.

[0011] The method according to claim 1 or 2, wherein the generated anaplerotic product enters the Krebs cycle at various time points as an intermediate such as, for example, acetyl-CoA, citrate, isocitrate, α-ketoglutarate, succinyl-CoA, and / or oxaloacetate.

[0012] A method for treating a patient having propionic acidemia (PA), methylmalonic aciduria (MMA), or fatty acid oxidation disorder and having an abnormally low amount of anaplerotic intermediates, the method comprising administering to the patient a structure A-B or B-A': a. [For the treatment of PA, in the structure, A is a dicarboxylic acid, tricarboxylic acid, or even-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid; A' is an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid; B is at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or to A' by an amide bond or an ester bond, and comprises a D-amino acid, a D-dipeptide of a D-amino acid, or a D-tripeptide], or a pharmaceutically acceptable salt thereof; b. For the treatment of MMA, in the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or even-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, citric acid, isocitric acid, oxaloacetic acid, and α-ketoglutaric acid; A' comprises an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid or 6-amino-hexanoic acid; B is at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or linked to A' by an amide bond or an ester bond, and comprises a D-amino acid, D-dipeptide of D-amino acid, or D-tripeptide], or a pharmaceutically acceptable salt thereof; or c. For the treatment of fatty acid oxidation disorders, in the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or even-chain or branched-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, even-chain fatty acid, or branched-chain fatty acid; A' comprises an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid, or 6-amino-2,4-dimethylheptanoic acid; B is at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Thr, D-Ile, D-Val, D-Asp, D-Asn, or D-Leu, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or linked to A' by an amide bond or an ester bond, and comprises a D-amino acid, D-dipeptide of D-amino acid, or D-tripeptide], or a pharmaceutically acceptable salt thereof A method comprising administering

[0013] Item 5. The method according to item 4, wherein the compound has an amount effective to normalize the level of an anaplerotic intermediate of structure A-B [in the structure, A comprises an adipic acid moiety or a methylmalonic acid moiety (not MMA); B is at least one amino acid selected from D-Ser, D-Ala, D-Lys, D-Leu, and D-His, linked to A by an amide bond or, in the case of D-Ser, by an amide bond or an ester bond, and comprising a D-amino acid, a D-dipeptide of a D-amino acid, or a D-tripeptide], or a pharmaceutically acceptable salt thereof.

[0014] Item 6. The method according to any one of items 1 to 5, wherein the patient has propionic academia (PA); transient methylmalonic academia due to transcobalamin receptor deficiency (MMA); cblA type methylmalonic academia; cblB type methylmalonic academia; medium-chain acyl-CoA dehydrogenase (MCAD) deficiency; very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency; trifunctional protein (TFP) deficiency; long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency; carnitine palmitoyltransferase II (CPT II) deficiency; glutaric academia I (GA I or GA1); or glutaric academia II (GA I or GA2).

[0015] Item 7. The method according to any one of items 1 to 5, wherein the compound comprises the types of moieties listed in FIGS. 17A and 17B, and the compound is used for the treatment of the corresponding recommended indications in FIGS. 17A and 17B and, where relevant, is optionally contraindicated for the treatment of the corresponding diseases as shown in FIGS. 17A and 17B.

[0016] Item 8. The method according to any one of items 1 to 7, wherein the succinylation of succinyl-CoA or lysine in the patient is decreased.

[0017] Item 9. The method according to any one of Items 1 to 5, wherein the patient has glutaric acidemia type I (GA I or GA1) excluding glutaric acid or lysine in the compound structure, or glutaric acid or lysine, fatty acids in the compound structure, and glutaric acidemia type II (GA 2 or GA II) excluding fatty acids and branched-chain amino acids that require ETF or ETF dehydrogenase for the degradation of branched-chain amino acids. GA II cannot have Ile, Leu, Val, Lys, glutaric acid or adipic acid, branched-chain or odd-chain fatty acids, or any saturated fatty acid having 4 or more carbon atoms.

[0018] Item 10. The method according to any one of Items 1 to 9, wherein B comprises one or more of D-Ser, D-Ala, D-Lys, D-Leu, and / or D-His.

[0019] Item 11. The method according to any one of Items 1 to 10, wherein B is selected from -D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-Ser-D-His, -D-Ala-D-Ser, or -D-Ala-D-His, and D-Ser is linked by an amide bond (-N-bond) or an ester bond (-O-bond).

[0020] Item 12. The compound has the structure:

Chemical formula

[0021] Claim 13 The compound has the structure:

Chemical formula

[0022] Item 14. The method according to any one of Items 1 to 9, wherein the compound is selected from PMA001, for example, 4-hydroxyl adipic acid - O - D - Ser; PMA002, for example, 4-hydroxyl adipic acid - O - D - Ser - D - Ala; PMA003, for example, 4-hydroxyl adipic acid - O - D - Ser - D - Ala; PMA004, for example, 2-ketoglutaric acid - D - 2-hydroxyglycine - D - Ala; PMA005, for example, 2-ketoglutaric acid - O - D - Ser - D - Ala; PMA006, for example, 4-keto adipic acid - O - L - Ser; PMA007.1, for example, 4-keto adipic acid - O - D - Ser - D - His; PMA008, for example, 2-ketoglutaric acid - O - D - Ser - D - His; PMA009, for example, 2-ketoglutaric acid - D - Ala - D - His; PMA010.1, for example, 4-keto adipic acid - D - Ala - D - His; PMA011, for example, methylmalonic acid - O - D - Ser - D - His; PMA012, for example, methylmalonic acid - D - Ala - D - His; PMA013, for example, adipic acid - D - Ala - D - Ser - D - His; PMA014, for example, adipic acid - D - Ser - D - His; PMA019, for example, methylmalonic acid - D - Leu - D - His; and PMA020, for example, methylmalonic acid - D - Lys - D - His.

[0023] Item 15. The method according to any one of Claims 1 to 9, wherein the compound is PMA010 (adipic acid - D - Ala - D - His).

[0024] Item 16. The method according to any one of Items 1 to 9, wherein the compound is PMA007 (adipic acid - O - D - Ser - D - His).

[0025] Item 17. The method according to any one of Items 1 to 9, wherein the compound is PMA011 (methylmalonic acid - D - Ala - D - His) rather than MMA.

[0026] Item 18. The method according to any one of Items 1 to 9, wherein the compound is PMA019 (methylmalonic acid - D - Leu - D - His) rather than MMA.

[0027] Item 19. The method according to any one of Items 1 to 9, wherein the compound is PMA020 (methylmalonic acid - D - Lys - D - His) rather than MMA.

[0028] Item 20. The method according to any one of Items 1 to 11, wherein the patient has propionic academia and A is methylmalonic acid excluding propionogenic amino acids or fatty acids.

[0029] Item 21. The method according to Item 20, wherein the patient does not have methylmalonic academia excluding methylmalonic acid.

[0030] Item 22. The method according to any one of Items 1 to 21, wherein the patient has propionic academia or methylmalonic academia, and the method further comprises administering to the patient an inhibitor that blocks the formation of propionyl - CoA or methylmalonyl - CoA.

[0031] Item 23. The method according to Item 22, wherein the inhibitor that blocks the formation of propionyl - CoA or methylmalonyl - CoA is 2,2 - dimethylbutyric acid or sodium 2,2 - dimethylbutyrate.

[0032] Item 24. The method according to any one of Items 1 to 21, further comprising administering to the patient an inhibitor that restricts the production of propionyl - CoA or methylmalonyl - CoA from various sources, for example, co - administering as adjuvant therapy to the patient.

[0033] Item 25. The method according to Item 24, wherein the inhibitor is an inhibitor of propionyl - CoA or methylmalonyl - CoA formation such as HST5040.

[0034] Item 26. Compound having structure A-B or B-A' [in the structure, it contains a dicarboxylic acid, tricarboxylic acid, or a linear or branched fatty acid moiety selected from adipic acid, 3-hydroxy-adipic acid, 3-ketoadipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, linear fatty acid, or branched fatty acid; A' contains a linear or branched fatty acid moiety selected from 6-hydroxy-hexanoic acid (hydroxyl group linked to B carboxylic acid as an ester bond), 6-amino-hexanoic acid (linked to B carboxylic acid via an amide bond), or 6-amino-2,4-dimethylheptanoic acid (linked to B carboxylic acid via an amide bond); B is an amino acid, D-dipeptide of an amino acid, or D-tripeptide containing at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or linked to A' by an ester bond or an amide bond], or a pharmaceutically acceptable salt thereof.

[0035] Item 27. The compound according to claim 26, having structure A-B [in the structure, A contains an adipic acid moiety or a methylmalonic acid moiety; B is a D-amino acid, D-dipeptide of a D-amino acid, or D-tripeptide containing at least one amino acid selected from D-Ser, D-Ala, D-Lys, D-Leu, and D-His, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond], or a pharmaceutically acceptable salt thereof.

[0036] Item 28. The compound according to claim 26, wherein B contains one or more of D-Ser, D-Ala, D-Lys, D-Leu, and / or D-His.

[0037] Item 29. The compound according to Item 28, wherein B is selected from -D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-Ser-D-His, -D-Ala-D-Ser, or -D-Ala-D-His, and wherein D-Ser is linked by an amide bond (-N-bond) or an ester bond (-O-bond).

[0038] Item 30. Structure:

Chemical formula

[0039] Claim 31 Structure: [Chemical formula] [In the structure, R5 is linked via an ester bond (-O-bond) or an amide bond (-N-bond) and contains 1 to 3 D-amino acids selected from D-Ser, -O-D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, and D-Val, or is one of -D-Ser, -O-D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-O-D-Ser, -D-His-D-Ser-D-Ala, -D-His-O-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -O-D-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -O-D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-O-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-O-D-Ser, -D-Ser-D-His, -O-D-Ser-D-His -D-Ser-D-Ala, -O-D-Ser-D-Ala-D-Ala-D-Ser, -D-Ala-O-D-Ser, -D-Ala-D-His, -D-Leu-D-His, or -D-Lys-D-His] The compound according to claim 26, having

[0040] Item 32. A compound according to item 26, selected from PMA001, for example, 4-hydroxyl adipic acid - O - D - Ser; PMA002, for example, 4-hydroxyl adipic acid - O - D - Ser - D - Ala; PMA003, for example, 4-hydroxyl adipic acid - O - D - Ser - D - Ala; PMA004, for example, 2-ketoglutaric acid - D - 2-hydroxyglycine - D - Ala; PMA005, for example, 2-ketoglutaric acid - O - D - Ser - D - Ala; PMA006, for example, 4-ketoadipic acid - O - L - Ser; PMA007.1, for example, 4-ketoadipic acid - O - D - Ser - D - His - succinyl CoA; PMA008, for example, 2-ketoglutaric acid - O - D - Ser - D - His; PMA009, for example, 2-ketoglutaric acid - D - Ala - D - His; PMA010.1, for example, 4-ketoadipic acid - D - Ala - D - His; PMA011, for example, methylmalonic acid - O - D - Ser - D - His; PMA012, for example, methylmalonic acid - D - Ala - D - His; and PMA013, for example, adipic acid - D - Ala - D - Ser - D - His; PMA014, for example, adipic acid - D - Ser - D - His; PMA019, for example, methylmalonic acid - D - Leu - D - His; and PMA020, for example, methylmalonic acid - D - Lys - D - His.

Brief Description of the Drawings

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[0042] Detailed description The use of numerical values in the various ranges specified in this application, unless otherwise expressly indicated, both the minimum and maximum values within the recited ranges are described as approximate values as if preceded by the word "about". Thus, minor variations above and below the recited ranges can be used to achieve substantially the same results as the values within the range. Also, unless otherwise indicated, the disclosure of a range is intended to be a continuous range including every value between the minimum and maximum values. As used herein, "a" and "an" refer to one or more.

[0043] As used herein, "comprising" is open-ended and can be synonymous with "including", "containing", or "characterized by". The term "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics. The term "consisting of" excludes elements, steps, or components not specified in the claim. As used herein, embodiments "comprising" one or more of the recited elements or steps include, but are not limited to, embodiments "consisting essentially of" and "consisting of" these recited elements or steps.

[0044] As used herein, the terms "patient" or "subject" refer to members of the animal kingdom including, but not limited to, humans, and "mammal" refers to all mammals, but is not limited thereto.

[0045] This specification provides compounds and methods for the treatment of certain metabolic diseases that involve or are caused by one or more anaplerotic reactions or pathway deficiencies in patients who produce anaplerotic compounds as a symptom or sequela. Such diseases include, for example, but are not limited to, propionic academia, methylmalonic academia, fatty acid oxidation (e.g., β-oxidation) disorders, or deficiencies in certain Krebs cycle (Figure 2)-related enzymes, such as pyruvate dehydrogenase deficiency (see Figures 17A and 17B). Compounds useful in the methods described herein comprise an adipic acid or methylmalonic acid moiety linked via an amide bond to a D-dipeptide or D-tripeptide consisting of the D-amino acid forms of a single D-amino acid, His (histidine), Ala (alanine), Ser (serine), Lys (lysine), Glu (glutamic acid), Gln (glutamine), Asp (aspartic acid), Asn (asparagine), Leu (leucine), isoleucine (Ile), threonine (Thr), and Val (valine). When Ser is present, it may form an ester by O-linkage with an R group or may form a standard peptide bond by O-linkage with its amine group. Various compounds are further described below. When administered to a patient, the compounds are broken down into their components, supplementing the patient's anaplerotic reactions and pathways and thus addressing the cause, symptoms, or sequela of a particular disease. Because the lack of anaplerotic compounds varies depending on the metabolic disease, different compounds may be selected to assist patients with different diseases.

[0046] The metabolic pathways of different patients should be understood to potentially break down compounds in different ways depending on, among other factors, the patient's genetics, nutrition, health, and activity. That being said, a compound is expected to be metabolized primarily into an intermediate that replenishes a specific anaplerotic compound produced via an anaplerotic pathway in a given patient. For example, an adipic derivative (i.e., adipic acid or a derivative thereof as described herein) is expected to primarily supply one acetyl-CoA and one succinyl-CoA in a patient. Methylmalonic acid is expected to supplement the patient's succinyl-CoA. D-amino acids are not directly used for protein synthesis or structure but are included in the structure because they are metabolized to a deaminated form. D-His is expected to increase α-ketoglutarate levels and thus function as a succinyl-CoA precursor in the TCA cycle. D-Ala undergoes deamination to form pyruvate, which is either broken down by pyruvate dehydrogenase for use in the TCA cycle, carboxylated to form oxaloacetate (see Figure 2), or can be used in gluconeogenesis. D-Ser is deaminated and / or broken down to form pyruvate or glycine or may follow other pathways. All amino acids may be deaminated to a keto form and then reaminated to an L-form, but the loss to the L-form for proteins and other anabolic pathways should not significantly affect the bulk that is further catabolized.

[0047] As used herein, the terms "treating" or "treatment" can refer to a beneficial or particular result such as the improvement of one or more functions or symptoms of a disease. The terms "treating" or "treatment" can also include, but are not limited to, the alleviation or improvement of one or more symptoms of propionic academia, methylmalonic academia, or a fatty acid oxidation (e.g., β-oxidation) disorder, or the normalization of a clinically relevant marker. "Treatment" can also mean extending the survival period as compared to the survival period expected in the absence of treatment. As used herein, "transdermal" means "through the skin".

[0048] With respect to a disease marker or symptom, "decrease" can refer to a clinically relevant and / or statistically significant decrease in such a level. The decrease can be, for example, a decrease of at least 10%, at least 20%, at least 30%, at least 40%, or more, a decrease to a level recognized as within the normal range of individuals without such a disorder, or a decrease to below the detection level of the assay. The decrease can be a decrease to a level recognized as within the normal range for individuals without such a disorder, which can also be referred to as normalization of the level. The decrease can be normalization of the level of a sign or symptom of a disease, i.e., a decrease in the difference between the target level of the sign of the disease and the normal level of the sign of the disease (e.g., to the upper normal level if the target value has to decrease to reach the normal value, and to the lower normal level if the target value has to increase to reach the normal level). The methods described herein can include, for example as described herein, clinically relevant alleviation of any symptom or normalization of the level of a clinical marker of a disease.

[0049] "Therapeutically effective amount", as used herein, can include an amount of a compound as described herein that, when administered to a subject having a disease, is sufficient to effect treatment of the disease (e.g., by decreasing, ameliorating or maintaining an existing disease or one or more symptoms of the disease, including normalization of any relevant clinical marker). The "therapeutically effective amount" can vary depending on the method of administration of the composition, the disease and its severity, and the medical history, age, weight, family history, genetic constitution, type of prior treatment or concomitant treatment (if any), and other individual characteristics of the subject being treated.

[0050] The "therapeutically effective amount" can also include an amount of an agent that provides a local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. The compounds described herein can be administered in an amount sufficient to provide a reasonable benefit / risk ratio applicable to such treatment.

[0051] As used herein, the term "pharmaceutically acceptable carrier" can refer to a liquid or solid diluent, excipient, vehicle, manufacturing aid (e.g., lubricants such as magnesium talc, calcium stearate or zinc stearate), or solvent encapsulation material, etc., that is involved in the conveyance or transport of a subject compound from one organ or body part to another. Each carrier can be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and does not harm the subject being treated. Some non-limiting examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricants such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; (22) bulking agents such as polypeptides and amino acids; (23) serum components such as serum albumin, HDL and LDL; and (24) other non-toxic compatible substances used in pharmaceutical formulations.

[0052] Any pharmaceutically acceptable salts of the compounds described herein are also usable in the methods described herein. Pharmaceutically acceptable salt forms of the compounds described herein can be prepared by conventional methods known in the pharmaceutical art and include salts that are veterinarily acceptable as a class. For example, but not limited to, when the compound comprises a carboxylic acid group, a suitable salt can be formed by reacting the compound with a suitable base to provide the corresponding base addition salt. Non-limiting examples include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine, and N-methylglutamine.

[0053] Non-limiting examples of pharmaceutically acceptable salts include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganates, potassium salts, sodium salts, and zinc salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines such as natural substituted amines, cyclic amines, and salts of basic ion exchange resins such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris-(hydroxymethyl)-methylamine (tromethamine).

[0054] Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, aspartate, benzoate, besylate (benzenesulfonate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, galacterate, galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, and phthalate.

[0055] Multiple salt forms are also considered to be pharmaceutically acceptable salts. General non-limiting examples of multiple salt forms include bitartrate, diacetate, difumarate, dimenhydrinate, diphosphate, disodium, and trihydrochloride.

[0056] Thus, "pharmaceutically acceptable salts," as used herein, is intended to mean an active ingredient (drug) comprising a salt form of any compound described herein. The salt form may impart improved and / or desirable pharmacokinetic / pharmacodynamic properties to the compounds described herein.

[0057] Organic compounds may form complexes with solvents in which they react or solvents in which they precipitate or crystallize. These complexes are known as "solvates". Complexes with water are known as "hydrates". Solvates of the compounds disclosed herein (e.g., compound A-B, or B-A') are contemplated. Also, those skilled in the art of organic chemistry will understand that many organic compounds can exist in two or more crystalline forms. For example, the crystalline form can differ by solvate. Accordingly, all crystalline forms of the compounds described herein (e.g., compound A-B, or B-A') or pharmaceutically acceptable solvates thereof are within the scope of the present invention (see generally, A.M. Healy, et al., Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals, Adv. Drug Deliv. Rev. 2017 Aug 1;117:25-46).

[0058] "Group" or "functional group" comprises, or consists of, an atom and / or grouping of bonds that impart chemical or physical properties to a molecule, or is a portion of a larger molecule. As used herein, "residue" refers to a portion of a compound or monomer such as adipic acid, 3-hydroxy-adipic acid, 3-ketoadipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid, D-Ser, D-Ala, D-Lys, D-Leu, D-His, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Val, or D-Thr that remains in a larger molecule such as a polymer chain or macromolecule described herein after incorporation of the compound or monomer into the larger molecule. A compound comprising residues of other smaller compounds such as adipic acid, methylmalonic acid, D-Ser, D-Ala, D-Leu, D-Lys, and D-His is said to be composed of such compounds. "Moiety" is a portion of a molecule and may comprise one or more functional groups and, in the case of an "active moiety", is a characteristic portion of a molecule or compound that imparts activity such as pharmacological or physiological activity as contrasted with an inactive portion of the molecule such as an ester of the active moiety or a salt of the active agent.

[0059] This specification describes compounds that are useful in treating propionic academia, methylmalonic academia, and fatty acid oxidation disorders. These compounds may be referred to as anaplerotic compounds or anaplerotic agents because of their usefulness in replenishing or supplementing metabolic intermediates that may be reduced in patients with metabolic disorders such as, for example, propionic academia, methylmalonic academia, or fatty acid oxidation disorders in anaplerotic therapy. The metabolic intermediate may be succinyl-CoA or other intermediates. For example, α-ketoglutaric acid and succinyl-CoA are required for various biochemical functions and thus it is desirable to replenish them from other sources including amino acid metabolism and other sources including odd-chain branched fatty acids. These compounds have the structure A-B or B-A’, where in the structure, “A” is a dicarboxylic acid, tricarboxylic acid, or straight-chain or branched-chain fatty acid selected from adipic acid, 3-hydroxy-adipic acid, 3-ketoadipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, straight-chain fatty acids, or branched-chain fatty acids, and “A’” is a straight-chain or branched-chain fatty acid moiety selected from 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid, or 6-amino-2,4-dimethylheptanoic acid.

[0060] "Adipic acid" is a substituted or unsubstituted straight-chain aliphatic dicarboxylic acid having a total of six carbon atoms. For example, adipic acid may be substituted with a hydroxyl group at the third carbon atom to form 3-hydroxyadipic acid, or may be substituted with a keto group at the third carbon atom to form 3-ketoadipic acid. "Glutaric acid" is a substituted or unsubstituted straight-chain aliphatic dicarboxylic acid having a total of five carbon atoms. For example, glutaric acid may be substituted with a hydroxyl group at the second carbon atom to form α-hydroxyglutaric acid, or may be substituted with a keto group at the second carbon atom to form α-ketoglutaric acid. "Succinic acid" is a substituted or unsubstituted straight-chain aliphatic dicarboxylic acid having a total of four carbon atoms. For example, succinic acid may be substituted with a hydroxyl group at the second carbon atom to form 2-hydroxy succinic acid, or may be substituted with a keto group at the second carbon atom to form 2-ketosuccinic acid. "Citric acid" is a substituted or unsubstituted tricarboxylic acid having a hydroxy substituent at the second carbon. For example, citric acid may be further substituted with a hydroxyl group to form hydroxycitric acid.

[0061] In one aspect or one embodiment, the compound has the structure A-B, where "A" is an amino acid, a D-dipeptide of an amino acid, or a D-tripeptide containing at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu (D-glutamic acid), D-Gln (D-glutamine), D-Asp (D-aspartic acid), D-Asn (D-asparagine), D-Leu (D-leucine), D-Ile (D-isoleucine), D-Thr (D-threonine), or D-Val (D-valine), in combination with "B", which contains an adipic acid moiety or a methylmalonic acid moiety. "D-amino acid" is an amino acid in which the sterically hindered carbon α with respect to the amino group has a D-configuration. "D-dipeptide" is a peptide composed of two D-amino acid residues. "D-tripeptide" is a peptide composed of three D-amino acid residues. In one aspect or one embodiment, "B" is one to three amino acids selected from or including D-Ser, D-Ala, D-Lys, D-Leu, and / or D-His. Alternatively, "B" is -D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-Ser-D-His, -D-Ala-D-Ser, or -D-Ala-D-His, where D-Ser can be linked by an amide bond (-N-bond) or an ester bond (-O-bond). As another option, there are D-Leu and / or D-Lys which can be substituted with D-Ala or D-Ser.

[0062] In the compound structure A-B, A and B may be linked by an amide bond formed by reacting the carboxylic acid of A with the amine of B. In the case of D-Ser, A and B may be linked by an amide bond or an ester bond, where the amide bond is formed by reacting the carboxylic acid of A with the amine of D-Ser, and the ester bond is formed by reacting the carboxylic acid of A and the hydroxyl of D-Ser. In the compound structure B-A’, B and A’ may be linked by an ester bond or an amide bond, where the amide bond is formed by reacting the carboxylic acid of B with the amine of A’, and the ester bond is formed by reacting the carboxylic acid of B with the hydroxyl of A’. D-amino acids are not metabolized as L-enantiomers and thus D-amino acids may undergo conversion to anaplerotic compounds that may be depleted in patients with metabolic disorders such as propionic academia, methylmalonic aciduria, or fatty acid oxidation disorders.

[0063] Specific exemplary useful fatty acids for A and A’ include straight or branched chain, saturated or unsaturated C 4-24 fatty acids. Exemplary fatty acids are described in International Patent Publication No. WO2020 / 014428 A1, which disclosure is incorporated herein by reference and include heptanoyl, 2-methylheptanoyl, 2,6-dimethylheptanoyl, 4,8-dimethyldecanoyl, 6-amino-2,4-dimethylheptanoyl, linolenoyl, docosahexaenoyl, or eicosapentaenoyl fatty acid moieties. Other useful fatty acid moieties include C 18:3 , C 20:5 , or C 22:6 fatty acid moieties having double bonds at the ω3 and ω6 positions of C 18:3 , C 20:5 , or C 22:6 fatty acid moieties. Fatty acids are ω3 or ω6 (e.g., n-3) fatty acids, α-linolenoyl (e.g., C 18:3 ), docosahexaenoyl (e.g., C 22:6 ), and eicosapentaenoyl (e.g., C 20:5) It can be a fatty acid. The fatty acid can be of the odd type such as heptanoyl or nonanoyl, or of the even type such as linolenoyl, docosahexaenoyl, or eicosapentaenoyl. These long-chain unsaturated fatty acids can be useful for certain fatty acid oxidation disorders, such as medium-chain acyl-CoA dehydrogenase deficiency (MCADD). The fatty acid can be a medium-chain fatty acid (e.g., C 6-12 , except in the case of MCADD), or a short-chain (e.g., C 1-5 ) fatty acid.

[0064] Serine (Ser) other than carboxyl contains two reactive groups that can be used to link serine to a larger molecule, namely, the amine group at the Cα position (a in the following structure) or the carboxyl group (b in the following structure). Ser may conjugate (covalently bond) the amine thereof to the carboxyl group of the adipic acid moiety or the methylmalonic acid moiety to form an amide bond (「a」 in the following structure), or may form an ester bond (「b」 in the following structure) via the hydroxyl group of its R group. In this case, the O-bonded (ester-bonded) D-Ser is referred to herein as -O-D-Ser. It should be noted that in the following, the terminal amino acid is D-Ser, but one or more additional amino acids may optionally bind to Ser via a carboxyl group to form an amide (peptide) bond. The dashed bond line means a bond that links the drawn portion to the rest of the molecule (not shown). Chirality is not drawn.

Chemical formula

[0065] The compound has the structure:

Chemical formula

[0066] For example, when the serine residue is D-Ser and is linked to the adipic acid partial residue via its R group (-CH2OH, referred to herein as -O-D-Ser-), the compound has, for example, the structure:

Chemical formula

[0067] The compound has the structure:

Chemical formula

[0068] For example, when the serine residue is D-Ser and is linked to the methylmalonyl residue via its R group (-CH2OH, referred to herein as -O-D-Ser-), the compound has, for example, the structure:

Chemical formula

[0069] Non-limiting examples of such compounds include PMA001, for example, 4-hydroxyl adipic acid - O - D - Ser; PMA002, for example, 4-hydroxyl adipic acid - O - D - Ser - D - Ala; PMA003, for example, 4-hydroxyl adipic acid - O - D - Ser - D - Ala; PMA004, for example, 2-ketoglutaric acid - D - 2-hydroxyglycine - D - Ala; PMA005, for example, 2-ketoglutaric acid - O - D - Ser - D - Ala; PMA006, for example, 4-ketoadipic acid - O - D - Ser; PMA007.1, for example, 4-ketoadipic acid - O - D - Ser - D - His; PMA008, for example, 2-ketoglutaric acid - O - D - Ser - D - His; PMA009, for example, 2-ketoglutaric acid - D - Ala - D - His; PMA010.1, for example, 4-ketoadipic acid - D - Ala - D - His; PMA007, for example, methylmalonic acid - O - D - Ser - D - His; PMA011, for example, methylmalonic acid - D - Ala - D - His; PMA012, for example, methylmalonic acid - D - Ala - D - Ser - D - His; PMA013, for example, adipic acid - D - Ala - D - Ser - D - His; PMA014, for example, adipic acid - D - Ser - D - His, and PMA015, PMA016, PMA017, PMA018, PMA019, or PMA020, which are linked to R - D - lysyl - D - glutamyl - D - histidine (PMA015), R - D - lysyl - D - glutamine (PMA016), R - D - lysyl - D - aspartyl - D - histidine (PMA017), or R - D - lysyl - D - asparagine (PMA018), R - D - leucyl - D - histidine (PMA019), and R - D - lysyl - D - histidine (PMA020), and contain an R group selected from adipyl, glutaryl, succinyl, heptanoyl, 2,6 - dimethylheptanoyl, 4,8 - dimethylnonanoyl, and 6 - amino - 2,4 - dimethylheptanyl. Figures 1A - 1C, 5, and 6 show these exemplary structures.

[0070] Figures 17A and 17B show further examples of parts useful for A and B, describe the conditions of certain parts expected to be useful for the treatment of various indications, and include contraindications. More specifically, Figures 17A and 17B describe the functional contributions of potential sites that are anaplerotic in compounds of this class, as well as the mode of action and catabolic pathways. Potential D-amino acids can be used in combination with specific fatty acids. For PA and MMA, propiogenic amino acids and propiogenic fatty acids containing branched-chain and odd-chain amino acids and fatty acids are contraindicated.

[0071] In the treatment of propionic academia or methylmalonic academia, the method may further comprise co-administering to the patient, together with the above compounds, an inhibitor that blocks the formation of propionyl-CoA acid or methylmalonyl-CoA, respectively, in propionic academia or methylmalonic academia. Co-administration refers to, for example, administering a second active agent during the course of treatment with a first active agent as described above. The second active agent can be administered before, after, or simultaneously with the first active agent and can be formulated in the same unit dosage form. In one example, the inhibitor that blocks the formation of propionyl-CoA acid or methylmalonyl-CoA is 2,2-dimethylbutyric acid, sodium 2,2-dimethylbutyrate, or a formulation of 2,2-dimethylbutyric acid, or any inhibitor that limits the function of propionyl-CoA carboxylase.

[0072] In addition, the propionyl-CoA / methylmalonyl-CoA (P-CoA / MM-CoA) formation inhibitors described herein can be administered to patients as adjuvant therapy together with the compounds described herein. For example, the P-CoA / MM-CoA formation inhibitor can be HST5040 (see, for example, Armstrong et al. “Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia”, J. Med. Chem., 2021, 64: 5037-5048).

[0073] Propionic acidemia: Propionic acidemia is an autosomal recessive metabolic disorder. Propionic acidemia is caused by a deficiency of propionyl-CoA carboxylase (PCC), a mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to S-methylmalonyl-CoA. Propionyl-CoA is the end product of the catabolism of valine, isoleucine, methionine, and threonine and the β-oxidation of odd-chain fatty acids, and is also a byproduct of the β-oxidation of branched-chain fatty acids including phytanic acid and pristanic acid. PCC deficiency causes the accumulation of propionyl-CoA, which thiolytically decomposes to release toxic amounts of propionic acid, and at the same time, the final product succinyl-CoA of its downstream pathway, which is an intermediate of the TCA cycle, is lacking, critically causing dysfunction of the cycle. Not surprisingly, some fatty acid β-oxidation disorders and propionic acidemia present cardiomyopathy as a common phenotype.

[0074] Clinical features of PA: This disorder may present with feeding difficulties, lethargy, vomiting, and life-threatening acidosis, hypoglycemia, hyperammonemia, and / or bone marrow suppression within the first week of life, and the early-onset mortality rate is high. Severe hyperammonemia contributes to encephalopathy in acute neonatal diseases. Hyperammonemia is caused by inhibition of N-acetylglutamate synthesis by excessive propionyl-CoA, an activator of carbamoyl phosphate synthetase. The early-onset mortality rate is high. Equally common is a more chronic course, presenting with severe osteoporosis that causes feeding difficulties and episodes of vomiting, infection-induced ketoacidosis, growth retardation, and pathological fractures several months after birth. Developmental delay due to hyperammonemia or chronic disease is common. Metabolic stroke due to acute degeneration of the basal ganglia of the brain may occur during or between episodes of ketoacidosis. Cardiomyopathy, which can be rapidly fatal, occurs frequently and is carnitine-resistant. Pancreatitis, like chronic kidney disease, is recognized as a complication of this disease.

[0075] Treatment is directed at treating shock, acidosis, hypoglycemia, and hyperammonemia with fluids, bicarbonate, glucose, and dialysis. Dietary natural protein (or propionogenic amino acids) is instructed to be restricted to the amount necessary to support normal growth and development, and usually, the intake of natural protein is less than 1 g / kg / day. Generally, reliance on liver transplantation can reduce the risk of episodes of metabolic decompensation and recover cardiomyopathy.

[0076] Anaplerotic Therapy: The proof of concept that anaplerotic compounds can be therapeutic agents was reported more than 20 years ago using L-malate as an intermediate of the Krebs cycle. This study was conducted in vitro using a mitochondrial assay of rat liver. The researchers reported that treatment with L-malate decreased the level of propionyl-CoA in the mitochondrial matrix by 62% and the level of propionate by 46%. In clinical trials initiated in 2008, anaplerotic compounds such as glutamine, citrate, and ornithine α-ketoglutarate were tested in PA patients, and the authors concluded that citrate supplementation may be beneficial in some cases as it helps replenish depleted Krebs cycle intermediates. Although positive results have been obtained in these trials, the mode of delivery of these anaplerotic compounds to the target sites in mitochondria is likely to be a major obstacle for these compounds to achieve effective therapeutic outcomes.

[0077] Methylmalonic Aciduria (MMA) Methylmalonic aciduria can occur due to a hereditary deficiency of methylmalonyl-CoA mutase, which is an enzyme downstream of PCC and requires adenosylcobalamin. This enzyme is involved in the metabolic pathway that converts L-methylmalonyl-CoA to succinyl-CoA or catalyzes the biosynthesis of adenosylcobalamin from vitamin B12. When the latter deficiency occurs at a proximal stage that also impairs methylcobalamin synthesis, homocysteine accumulates due to the blockade of N5-methyltetrahydrofolate:homocysteine methyltransferase.

[0078] Clinical Picture of MMA: The clinical picture of complete methylmalonyl-CoA mutase deficiency includes symptoms common to propionic academia. Severe ketoacidosis, hyperammonemia, and thrombocytopenia are seen within days or weeks after birth. In patients with some residual mutase activity, various symptoms including intermittent ataxia, recurrent vomiting, failure to thrive, and developmental delay appear later. Life-threatening decompensated episodes, whether severe or mild, can usually be triggered by the complication of minor illnesses.

[0079] Patients with deficiencies in cblA and cblB usually have isolated methylmalonic aciduria, but it is somewhat milder. Mutations in the SUCLA gene, which encodes the ATP-forming subunit of the enzyme succinyl-CoA ligase in the Krebs cycle, are a new cause of methylmalonic aciduria. Affected patients have a severe phenotype that includes hypotonia, muscle atrophy, hyperkinesia, mental retardation, growth retardation, atrophy of the central and cortical regions of the brain, and atrophy of the basal ganglia. Mutations in the CblC gene cause combined methylmalonic aciduria and homocystinemia. CblC deficiency most often presents in infancy with severe clinical symptoms including basal ganglia necrosis, microcephaly, hypoplasia, intellectual disability, retinopathy, and megaloblastic anemia. CblD mutations cause a complex disorder such as that seen in CblC-deficient patients, but variants associated with isolated methylmalonic aciduria as well as isolated homocystinemia have also been identified. In patients with deficiencies in the CblE group and CblG group, only methylcobalamin biosynthesis is defective, and they present with homocystinuria without methylmalonic aciduria. In CblF deficiency, transport of B12 from lysosomes is defective, and methylmalonic aciduria and homocystinemia are combined. Similar to propionic academia, treatment during episodes of acute metabolic decompensation is first directed at treating shock, acidosis, hypoglycemia, and hyperammonemia, and then protein (especially propionogenic amino acids) is restricted. Carnitine is used for the treatment of secondary carnitine deficiency. Some of the patients treated in this way have a good course, but many do not, and they die in infancy during episodes of ketoacidosis. Liver transplantation or hepatorenal transplantation reduces the severity but cannot cure the disease.

[0080] Deficiencies in long-chain fatty acid oxidation cause a marked decrease in the lysine succinylation of mitochondrial proteins and are part of the pathological mechanism. Deficiencies in MCAD, VLCAD, LCHAD, TFP, and CPT II are the most common metabolic deficiencies identified by neonatal screening using tandem mass spectrometry.

[0081] Therapy for the treatment of patients with mitochondrial fatty acid β-oxidation deficiency, for example, for the treatment of patients with MCAD, VLCADD, LCHADD, TFPD, or CPT II deficiency, is necessary to minimize life-threatening episodes of decompensation, which occur in the majority of cases when frequent hospitalizations are required during the first two to three years of life. For pediatric patients, adults, and the elderly, a healthy and exercise-tolerant lifestyle is also important to avoid other common late-onset diseases. U.S. Patent No. 8,399,515 describes C5 and C15 fatty acids useful for the treatment of fatty acid disorders, and WO / 2000045649 describes C7 fatty acids, such as n-heptanoic acid, for the treatment of fatty acid disorders leading to the development of triheptanoin. Further and / or better compositions for the treatment of fatty acid disorders are desirable. As an alternative treatment to compensate for the depletion of succinyl-CoA, medium-chain branched-chain fatty acids have also been reported (US WO2020014428 A1).

Example

[0082] There are three major pathways that maintain succinyl-CoA at its physiologically optimal levels. These are the TCA cycle, amino acid catabolism, and β-oxidation of branched odd-chain fatty acids. It is important that these three pathways function properly. Deficiency of an enzyme that catalyzes any of these three pathways causes disease. The catabolism of propiogenic amino acids (valine, isoleucine, methionine and threonine) and the β-oxidation of branched odd-chain fatty acids produce propionyl-CoA. If propionyl-CoA is not properly supplied from any of these pathways, or if there is a significant impact on the supply of succinyl-CoA as in the case of PA and MMA, the metabolic pathway of the administered compound is fate-determined to degradation and is not directly useful as building blocks for the biosynthesis of larger active molecules, it is possible to replenish succinyl-CoA via the TCA cycle. The proposed building blocks of the compound include D-histidine + D-alanine or D-serine, the former directly supplies α-ketoglutaric acid which is a precursor of succinyl-CoA in the TCA cycle, D-alanine is fate-determined to be deaminated to pyruvic acid, pyruvic acid is decomposed by pyruvate dehydrogenase and is either fully utilized in the TCA cycle or can still be used for gluconeogenesis. D-serine can be deaminated, reaminated to L-serine, decomposed to glycine which may be useful for the binding with propionic acid, or can migrate to other pathways. Adipic acid or its derivatives (see below) are assumed to provide one acetyl-CoA and one succinyl-CoA.

[0083] Compound: Through the present disclosure, three compounds, dicarboxylic acid acyl-D-dipeptides, are designed as follows: (1) The structure above in Figure 5, adipic acid-D-O-Ser-D-His (PMA007), where the bond between adipic acid and D-Ser is through an ester bond and D-Ser and D-His are linked by a peptide bond. (2) The structure below in Figure 5, adipic acid-D-Ala-D-His (PMA010), where the bonds between the three moieties are through peptide bonds. (3) The structure above in Figure 6, methylmalonic-D-Ala-D-His (PMA011), where the bonds between the three moieties are through peptide bonds. Further, for two compounds, PMA019, the structure in the middle of Figure 6, methylmalonic acid-D-Leu-D-His and PMA020, the structure below in Figure 6, methylmalonic acid-D-Lys-D-His, limited tests have been conducted and data are available.

[0084] Materials and Methods Compound Synthesis: Acyl-D-dipeptide dicarboxylic acids; PMA007, PMA010, PMA011, PMA019, and PMA020 were synthesized by solid-phase synthesis on a Liberty Microwave Synthesizer (CEM Corporation, Matthews, 3100 Smith Farm Road, NC 28106) using an FMOC synthesis protocol (Peptide & Peptoid Synthesis Facility, University of Pittsburgh Health Sciences Core Research Facilities). Briefly, the synthesis was carried out by starting from the carboxyl terminus and proceeding towards the amino terminus, adding activated amino acid residues stepwise to a solid support (Wang resin). Activation of the amino acids was performed by DIC-Oxyma chemistry. At the end of the synthesis, peptide PMA010 was coupled to adipic acid and methylmalonic acid overnight using PyBop / DIPEA chemistry, respectively, and the coupling efficiency was confirmed by the ninhydrin test. Additionally, adipic acid was coupled to the Ser-hydroxyl group of compound PMA007 using PyBop / DMAP coupling conditions. Finally, the peptide was cleaved from the resin with reagent B (95% TFA, 2.5% TIS, and 2.5% H2O), and multiple ether extractions were performed. The crude peptide was analyzed, characterized, and purified by reverse-phase high-performance liquid chromatography (RP-HPLC, 486 and 600E by Waters Corporation), and later confirmed to have the correct mass by a Bruker Ultraflextreme MALDI Tof / Tof mass spectrometer.

[0085] Cell Lines and Cultures: All proof-of-concept tests were conducted in vitro using fibroblasts from patients with propionic acidemia and methylmalonic acidemia to test these two compounds. [Table 1]

[0086] Using the control fibroblast cell line FB826, the amount of detectable succinyllysine in "normal" cells was estimated using an anti-succinyllysine antibody.

[0087] Immunohistochemistry: Patient cells were cultured at a seeding density of 3 - 5×10 4 cells on cover glasses. The media for both the untreated and treated groups contained no glucose, no glutamine, and no pyruvate, and lipid-depleted FBS was used instead of normal FBS. Fluorescence intensities of 50 - 60 cells in each group were quantified using NIH Image J software. Immunocytochemistry of the fibroblast cell line from a propionic acidemia patient (Fb859) stained with anti-succinyllysine (green), anti-MTCO1 (red), or anti-TOMM20 antibody, and the nuclei were stained with DAPI (blue). Instrument: Zeiss LSM 710 confocal microscope. Tukey's multiple comparison test was used for statistical analysis. **** P < 0.0001. The [PMA010] (90 μM) treatment group was statistically compared with control cells grown in the presence of normal complete DMEM medium, untreated cells, and [PMA010] (30 μM) cells grown in the absence of glucose / pyruvate / L-glutamine.

[0088] Measurement of mitochondrial respiration by Seahorse: Fb859 cells were grown in normal DMEM medium until they reached 85 - 90% confluence. The cells were harvested and seeded at a density of 25,000 cells / 80 μl (n = 8 replicates) in a poly-D-lysine-coated XFeseahorse 96-well plate in normal DMEM medium and incubated overnight at 37 °C in a 5% CO2 incubator. The next day, the culture medium in the designated wells was replaced as follows and left for 72 hours: 180 μl of Specialty Media A (seahorse XFDMEM basal medium + 10% defatted FBS + glucose + sodium pyruvate + L-glutamine + 0.5 mM carnitine). 180 μl of Specialty Media B (seahorse XFDMEM basal medium + 10% defatted FBS + 0.5 mM carnitine, without adding glucose, sodium pyruvate, or L-glutamine). 180 μl of Specialty Media B contained the test compound. After 72 hours of incubation, in each of the designated wells, Specialty Media A and B were replaced with 180 μL of Seahorse XF DMEM basal medium containing glucose, sodium pyruvate, L-glutamine, or without any glucose, sodium pyruvate, or L-glutamine, and incubated at 37 °C for 1 hour in a CO2-free incubator before measurement. OCR was measured (Seahorse XF MitoStress test). Finally, the cells were lysed and the protein content was determined. The data were normalized to the protein concentration, and OCR was expressed as pmol / min / mg protein.

[0089] Detection of ETC components by Western blot: Using the same T75 flasks as above, the control was media A, and the untreated and treated cells were media B. The amount of the compound was appropriately added directly to the cell culture medium when the culture reached approximately 85 - 90% confluence. The cultures were grown at 37 °C / 5% CO2 for 72 hours and then harvested. The harvested cell pellets were stored at -80 °C until immunological and enzymatic assays of OXPHOS subunits and Western blot analysis. 1 - 1.5 ml of the medium samples were also stored at -80 °C.

[0090] Measurement of mitochondrial respiration: Control Fb826 cells and patient Fb859 cells were grown in normal DMEM medium without added glutamine until 85 - 90% confluent. Cells were harvested and seeded at a concentration of 25,000 cells / 80 μL in normal DMEM medium without added glutamine in poly-D-lysine-coated XFe Seahorse 96-well plates (n = 8 replicates) and incubated overnight in a 37 °C, 5% CO₂ incubator. The next day, the culture medium in the designated wells was replaced as follows and left for 72 hours: (1) 180 μL of special medium A (Seahorse XF DMEM basal medium supplemented with 10% delipidated (lipid-free) FBS, glucose, sodium pyruvate, L-glutamine, and 0.5 mM carnitine). (2) 180 ml of specialty media B (Seahorse XF DMEM basal medium, 10% delipidated FBS, and 0.5 mM carnitine, excluding glucose, sodium pyruvate, and glutamine). (3) 180 ml of specialty media B containing the "reference compounds" (30, 90, 150 μM) D-serine, D-histidine, or adipic acid, and combinations of 90 μM D-serine + D-histidine and adipic acid, or the test compounds 30 μM or 90 μM PMA007 or PMA010. After 72 hours of incubation, in each of the designated wells, Specialty media A and B were replaced with 180 μL of Seahorse XF DMEM basal medium containing glucose, sodium pyruvate, and L-glutamine, or excluding these three components or the test compound, and incubated at 37 °C for 1 hour in a CO₂-free incubator before measurement with an Agilent XFe Seahorse instrument. The oxygen consumption rate (OCR) was determined (Seahorse XF MitoStress test). Finally, the cells were lysed and the protein content was determined. The data were normalized against the protein concentration, and the OCR is expressed as pmol / min / mg protein.

[0091] Determination of acylcarnitine levels: Media from control Fb826 cells and Fb859 cells from treated and untreated patients were harvested from either immunohistochemistry cultures or Seahorse oxygen consumption 96-well plate assays and analyzed for levels of short-chain acylcarnitines + propionylglycine and hydroxypropionylglycine using a triple quadrupole API4000 mass spectrometer (AB Sciex™, Framingham, MA) equipped with an ExionLC™ 100 HPLC system (Shimadzu Scientific Instruments™, Columbia, MD) as previously reported.

[0092] Measurement of mitochondrial ROS production using MitoSOX Red as a superoxide indicator probe: Control fibroblasts (Fb826), fibroblasts from PA patients (Fb859, Fb900), and fibroblasts from GA II patients (Fb930, Fb961) were grown to 85 - 90% confluence in normal DMEM medium containing glucose / pyruvate / L - glutamine. Cells were harvested and seeded at a concentration of 25,000 cells / 80 μl in a 96 - well microplate with a transparent bottom and black walls that had been cell - culture - treated in normal DMEM medium containing glucose / pyruvate / L - glutamine (n = 3) and incubated overnight at 37 °C in a 5% CO2 incubator. The next day, in the designated wells, the culture medium was replaced as follows and left for 72 hours: 150 μl of normal DMEM (glucose + 10% FBS + sodium pyruvate + L - glutamine + 0.5 mM carnitine). For control fibroblasts and fibroblasts from patients with propionic acidemia, 150 μl of normal DMEM containing the test compounds (180 μM and 640 μM) PMA010 or PMA011 or PMA019 and (640 μM) PMA020. For Fb930 GA II patient fibroblasts, 150 μl of normal DMEM containing the test compound (600 μM and 1200 μM) PMA011, and for Fb961 GA II patient fibroblasts, 150 μl of normal DMEM containing (1200 μM) PMA011. After 72 hours of incubation, the wells were washed twice with 150 μL of Seahorse XF DMEM basal medium, and in each designated well, the following assay buffer (150 μL of seahorse XF DMEM medium containing glucose, sodium pyruvate, and glutamine) was used together with 5 μM of MitoSOX reagent and incubated for 15 minutes in the dark in a 37 °C CO2 - free incubator. After 15 minutes of incubation, the cells were washed twice with 150 μL of seahorse XF DMEM basal medium and replaced with the same measurement buffer as the wash buffer. Fluorescence was monitored at an excitation of 520 nm and an emission of 580 nm. Finally, the cells were lysed and the protein content was determined. The data were normalized against the protein concentration and the fluorescence was shown as MitoSOX Red (AFU) / mg protein.

[0093] Results and Discussion Five biomarkers were assessed to measure the efficacy of compounds at the cellular level in terms of lysine succinylation, Western blot patterns of specific OXPHOS subunits, O2 consumption rate parameters, analysis of C3 acylcarnitine species, and effects on reactive oxygen species.

[0094] Restoration of lysine succinylation: Figure 7 shows a comparison of lysine succinylation of cellular proteins visualized by immunofluorescence confocal microscopy in an untreated patient and a PA patient (Fb859) treated with PMA010 and PMA011, or the individual components of these two compounds, including adipic acid and methylmalonic acid compared to succinic acid. All treatments show a clear increase in green staining compared to untreated cells.

[0095] Figures 8A-8F compare lysine succinylation of cellular proteins visualized by immunofluorescence confocal microscopy in untreated and treated PA patients (Fb859). Cells were grown in medium lacking glucose, pyruvate, and glutamine, but containing lean FBS. Figure 8B shows the recovery of lysine succinylation (green) signal in the presence of D-serine, compared to untreated Fb859 in Figure 8A. Figure 8C shows the recovery of lysine succinylation (green) signal in the presence of 30 μM and 90 μM PMA007. Figure 8D shows the recovery of lysine succinylation (green) signal in the presence of 30 μM and 90 μM PMA010. The yellow color indicates colocalization of lysine succinylated proteins with the mitochondrial MTCO1 subunit stained with anti-MTCO1 antibody (red). DAPI (blue) is included as a counterstain. The D-serine and PMA007 treatment data in the bar graphs of Figure 8E are quantified from images in Figures 8A and 8B. The D-serine and PMA010 treatment data in the bar graphs of Figure 8E are quantified from images collected from the D-serine replicate treatment experiment images and images collected from Figure 8D of the PMA010 treatment.

[0096] Figures 9A - 9F are comparisons of lysine succinylation of cellular proteins visualized by immunofluorescence confocal microscopy in human HEK293 control cells, untreated and treated HEK293 PCCA - / - knockout cells. In Figures 9B, 9C, and 9D, the cells were grown in medium lacking glucose, pyruvate, and glutamine. Figure 9B shows that in the absence of glucose, pyruvate, and glutamine, a substantial loss of lysine succinylation (green) signal is seen in both control and knockout cells. However, when - / - the PCCA cells were treated with 30 μM and 90 μM of PMA007 (Figure 9C), or with 30 μM and 90 μM of PMA010 (Figure 9D), it was shown that the green color recovered and lysine succinylation was restored. Yellow indicates the co - localization of lysine - succinylated proteins and the mitochondrial MTCO1 subunit stained with an anti - MTCO1 (red) antibody. DAPI (blue) was included as a counterstain. The bar - graph PMA007 - treatment data in Figure 9E quantifies the image in Figure 9C compared to the untreated control in Figure 9B. The bar - graph PMA010 - treatment data in Figure 9F quantifies the image in Figure 9D compared to the untreated control in Figure 9B.

[0097] Deficiency of ETC subunits in PA and MMA: Figure 10 shows a decrease in the signals of normal levels of control Fb826 and various ETC components in PA and MMA cells, specifically, Complex III subunit Core 2 48 kDa (UQCRC2), Complex IV subunit II 22 kDa (COXII) (worst in Fb959), and Complex I subunit NDUFB8 18 kDa. The band intensities of the above - mentioned ETC subunits were collectively used as biomarkers to observe changes due to treatment (see below).

[0098] Figure 11 shows the most prominent correction of signals of complex III subunit core 2 48 kDa (UQCRC2), complex IV subunit II 22 kDa (COXII), and complex I subunit NDUFB8 18 kDa in propionic academia (PA) cell line Fb859 compared to methylmalonic academia (MMA) cell line Fb857. PMA010 seems to have a better effect compared to PMA007. The complex II subunit core 2 (UQCRC2) was improved in untreated cells (containing no glucose, pyruvate, or fat in the medium).

[0099] Oxygen consumption parameters: Figures 12A - 12F show the changes in oxygen consumption rate with the addition of various inhibitors of the ETC in response to treatment with D - serine, D - histidine, adipic acid, PMA007, and PMA010 in PA patient cells Fb859, compared to the response when treated with individual components at 30 μM and 90 μM for 72 hours. Data are shown as mean ± SD. The number of replicates n = 5 - 8. The data were tested for normal distribution by the Shapiro - Wilk test. The variances were homogeneous (p>0.05), and the data followed a normal distribution (p>0.05). * P < 0.05, *** P < 0.01, *** P < 0.001 (After one - way analysis of variance (ANOVA), Tukey's post - hoc multiple range test was performed when F was significant). ns: no significance. Overall, the oxygen consumption parameters were improved in the presence of test compounds compared to individual components excluding adipic acid, D - serine, and D - histidine. More detailed studies are needed to determine the importance of the D - amino acid component of PMA family compounds in replenishing the Krebs cycle intermediates of the compounds compared to their role as carriers of dicarboxylic acid components.

[0100] O2 consumption parameters: Figures 13A - 13H, changes in oxygen consumption rate due to the addition of various inhibitors in response to treatment of PA patient cells Fb859 with PMA010 (Figures 13A - 13D) and PMA011 (Figures 13E - 13J). The data in these figures are presented as the rate of change relative to untreated cells. Since basal respiration can represent oxygen consumption at rest and is a function of cellular stress, but the change in spare respiratory capacity is significantly 3 - 4 times that of untreated cells, the effectiveness of these two compounds in improving cellular bioenergy is shown.

[0101] Evidence of acylcarnitine: Figures 14A - 14D, quantification of propionylcarnitine (Figure 14A), propionylglycine (Figure 14B), hydroxypropionylcarnitine (Figure 14C), and hydroxypropionylglycine (Figure 14D) in the medium of Fb859 cells and HEK293 PCCA - / - cells containing PMA007 or PMA010. The overall decrease detected in propionyl - CoA alternative metabolites is important as a major biomarker for this disease. The thiotolysis of excess propionyl - CoA to acid results in carnitine and glycine acting as detoxifying agents and being mainly converted to four metabolites in the liver. PMA010 - / - appears to be more effective in HEK293 PCCA cells, causing a decrease in propionylcarnitine (59% decrease), propionylglycine (41% decrease), and hydroxypropionylglycine (80% decrease). Medium samples were processed using mass spectrometry as shown in the "Materials and Procedures" below.

[0102] Evidence of the effect of PMA compounds in reducing detectable reactive oxygen species (ROS) in PA and GA II cells: Figures 15A - 15D show the levels of ROS, a biomarker associated with the generation of cellular stress in untreated PA cells, and the effects of treatment with various amounts of PMA010, PMA011, PMA019, and PMA020 on ROS generation in control FB826 (Figure 15A), FB859 PA cells (Figure 15B), and FB900 PA cells (Figure 15C). PMA010 caused a significant decrease in ROS detected in control cells (FB826) (Figure 15A) and FB900, another PA cell line (Figure 15C), and PMA011 was similarly effective in FB900 (Figure 15C). A preliminary test of the effect of PMA011 on GA II (glutaric acidemia II) FB930 and FB961 cell lines also showed a significant decrease in ROS when treated compared to untreated (Figure 15D).

[0103] Evidence of the decrease in lysine succinylation in fatty acid β - oxidation disorders: Figure 16 shows, as indicated, a significant decrease in the antigenic signal of succinyl - lysine (green staining), i.e., marked hypo - succinylation of lysine, in fatty acid oxidation disorders. Of note in the control normal cell line is that yellow shows the overlap of the signals for succinyl - lysine (green) and anti - MTCO1 (mitochondrial marker, red). In the TFP, CPTII, and VLCAD cell lines, red is dominant, indicating a decrease in lysine succinylation.

[0104] Conclusion: The results are consistent and clearly show the effectiveness of three compounds on PA cells (propionyl-CoA carboxylase deficient) at the molecular level in terms of being a rich source of succinyl CoA, and PMA010 shows slightly better performance in the in vitro model. Propionylcarnitine in the medium seems to have a slight decrease of 15%, but under the test conditions used, since the cells depleted glucose, pyruvate, or fatty acids, they had to use amino acids as energy, so propionylcarnitine was originally artificially high. In the case of MMA, the performance of the compound is not so remarkable, and it is presumed that this is due to methylmalonyl-CoA competing to modify the same reactive lysine site that succinyl-CoA targets. This suggests that while PCC inhibitors limit the accumulation of methylmalonyl-CoA, they can act synergistically with PMA010 to improve the deficiency of succinyl-CoA.

[0105] The present invention has been described with reference to specific exemplary embodiments, dispersible compositions, and their uses. However, those skilled in the art will recognize that various substitutions, modifications, or combinations of any of the exemplary embodiments can be made without departing from the spirit and scope of the present invention. Accordingly, the present invention is not limited by the description of the exemplary embodiments, but rather by the appended claims as originally filed.

Claims

Claim 1 A method for providing an anaplerotic compound to a patient in need, comprising administering to said patient a compound having the structure A-B or B-A': 〔In the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or a linear or branched fatty acid moiety selected from adipic acid, 3-hydroxy-adipic acid, 3-ketoadipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, linear fatty acid, or branched-chain fatty acid; A' comprises a linear or branched fatty acid moiety selected from 6-hydroxy-hexanoic acid (hydroxyl linked to the B carboxylic acid as an ester bond), 6-amino-hexanoic acid (linked to the B carboxylic acid via an amide bond), or 6-amino-2,4-dimethylheptanoic acid (linked to the B carboxylic acid via an amide bond); B is an amino acid, D-dipeptide of D-amino acid, or D-tripeptide comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val, which is linked to A by an amide bond, or in the case of D-Ser by an amide bond or an ester bond, or linked to A' by an ester bond or an amide bond〕 or a pharmaceutically acceptable salt thereof. Claim 2 wherein said compound has the structure A-B: 〔In the structure, A comprises an adipic acid moiety or a methylmalonic acid moiety; B comprises 1 to 3 D-amino acids selected from D-Ser, D-Ala, D-Lys, D-Leu, or D-His, which is linked to A by an amide bond, or in the case of D-Ser by an amide bond or an ester bond〕 or a pharmaceutically acceptable salt thereof, for the treatment of fatty acid oxidation disorders, according to claim 1. Claim 3 The method according to claim 1 or 2, wherein the generated anaplerotic product enters the Krebs cycle at various times as an intermediate such as, for example, acetyl-CoA, citric acid, isocitric acid, α-ketoglutaric acid, succinyl-CoA, and / or oxaloacetic acid. Claim 4 A method for treating a patient having propionic acidemia (PA), methylmalonic aciduria (MMA), or fatty acid oxidation disorder and having an abnormally low amount of anaplerotic intermediates, comprising administering to said patient a structure A-B or B-A': a. For the treatment of PA, in the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or even-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid; A' comprises an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid; B is a D-amino acid, D-dipeptide of a D-amino acid, or D-tripeptide comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu, linked to A by an amide bond, or in the case of D-Ser by an amide bond or an ester bond, or to A' by an amide bond or an ester bond), or a pharmaceutically acceptable salt thereof; b. For the treatment of MMA, in the structure, A comprises a dicarboxylic acid, tricarboxylic acid, or even-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, citric acid, isocitric acid, oxaloacetic acid, and α-ketoglutaric acid; A' comprises an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid or 6-amino-hexanoic acid; B is a D-amino acid, D-dipeptide of a D-amino acid, or D-tripeptide comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu, linked to A by an amide bond, or in the case of D-Ser by an amide bond or an ester bond, or to A' by an amide bond or an ester bond), or a pharmaceutically acceptable salt thereof; or c. For the treatment of fatty acid oxidation disorders, in the structure, A is a dicarboxylic acid, tricarboxylic acid, or an even-chain or branched-chain fatty acid moiety selected from adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, even-chain fatty acids, or branched-chain fatty acids; A' is an even-chain dicarboxylic acid or fatty acid moiety selected from 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid, or 6-amino-2,4-dimethylheptanoic acid; B is at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Thr, D-Ile, D-Val, D-Asp, D-Asn, or D-Leu, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or linked to A' by an amide bond or an ester bond, and comprises a D-amino acid, a D-dipeptide of a D-amino acid, or a D-tripeptide], or a pharmaceutically acceptable salt thereof A method comprising administering the same

5. The method according to claim 4, wherein the compound is a compound having the structure A-B in an amount effective to normalize the level of the anaplerotic intermediate 〔In the structure, A comprises an adipic acid moiety or a methylmalonic acid moiety B is a D-amino acid, a D-dipeptide of a D-amino acid, or a D-tripeptide comprising at least one amino acid selected from D-Ser, D-Ala, D-Lys, D-Leu, and D-His, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond〕 The method according to claim 4, which is a compound having the same, or a pharmaceutically acceptable salt thereof

6. The method according to any one of claims 1 to 5, wherein the patient has propionic academia (PA); transient methylmalonic academia (MMA) due to transcobalamin receptor deficiency; cblA type methylmalonic academia; cblB type methylmalonic academia; medium-chain acyl-CoA dehydrogenase (MCAD) deficiency; very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency; trifunctional protein (TFP) deficiency; long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency; carnitine palmitoyltransferase II (CPT II) deficiency; glutaric academia I (GA I or GA1); or glutaric academia II (GA II or GA2).

7. The method according to any one of claims 1 to 5, wherein the compound comprises the types of moieties listed in FIGS. 17A and 17B, the compound is used for the treatment of the corresponding recommended indications in FIGS. 17A and 17B, and is contraindicated for the treatment of the corresponding diseases as shown in FIGS. 17A and 17B, where relevant, as the case may be.

8. The method according to any one of claims 1 to 7, wherein the succinylation of succinyl-CoA or lysine in the patient is reduced.

9. The method according to any one of claims 1 to 5, wherein the patient has glutaric academia I (GA I or GA1) excluding glutaric acid or lysine in the compound structure, or glutaric acid or lysine, fatty acids and branched-chain amino acids in the compound structure, and glutaric academia II (GA II or GA2) excluding fatty acids and branched-chain amino acids that require ETF or ETF dehydrogenase for the breakdown of fatty acids and branched-chain amino acids in the compound structure.

10. The method according to any one of claims 1 to 9, wherein B comprises one or more of D-Ser, D-Ala, D-Lys, D-Leu, and / or D-His.

11. The method according to any one of claims 1 to 10, wherein B is selected from -D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-Ser-D-His, -D-Ala-D-Ser, or -D-Ala-D-His, and D-Ser is linked by an amide bond (-N-bond) or an ester bond (-O-bond).

12. The method according to any one of claims 1 to 9, wherein the compound has the structure: 【Chemical 1】 〔In the structure, R １ and R ２ are independently oxygen which is connected by H, hydroxyl, or a double bond to form a keto moiety, and at least one of R １ and R ２ is H, and R ３ is linked via an ester bond (—O— bond) or an amide bond (—N— bond) and comprises 1 to 3 D-amino acids selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, and D-Val, or is one of —D-Ser, —O—D-Ser, —D-Ala, —D-His, —D-His—D-Ala—D-Ser, —D-His—D-Ala—O—D-Ser, —D-His—D-Ser—D-Ala, —D-His—O—D-Ser—D-Ala, —D-Ser—D-His—D-Ala, —O—D-Ser—D-His—D-Ala, —D-Ser—D-Ala—D-His, —O—D-Ser—D-Ala—D-His, —D-Ala—D-Ser—D-His, —D-Ala—O—D-Ser—D-His, —D-Ala—D-His—D-Ser, —D-Ala—D-His—D-Ser, —D-His—D-Ala, —D-His—D-Ser, —D-His—O—D-Ser, —D-Ser—D-His, —D-Ala—O—D-Ser, or —D-Ala—D-His〕

13. The method according to any one of claims 1 to 9, wherein the compound has the structure:

14. 【Chemical Formula 2】 〔In the structure, R ５ is linked via an ester bond (-O-bond) or an amide bond (-N-bond) and comprises 1 to 3 D-amino acids selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, and D-Val, or is one of -D-Ser, -O-D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-O-D-Ser, -D-His-D-Ser-D-Ala, -D-His-O-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -O-D-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -O-D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-O-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-O-D-Ser, -D-Ser-D-His, -D-Ala-O-D-Ser, -D-Ala-D-His, -D-Leu-D-His, or -D-Lys-D-His〕 The method according to any one of claims 1 to 9, wherein the compound is PMA001, for example, 4-hydroxyl adipic acid - O - D-Ser; PMA002, for example, 4-hydroxyl adipic acid - O - D-Ser-D-Ala; PMA003, for example, 4-hydroxyl adipic acid - O - D-Ser-D-Ala; PMA004, for example, 2-ketoglutaric acid - D-2-hydroxyglycine - D-Ala; PMA005, for example, 2-ketoglutaric acid - O - D-Ser-D-Ala; PMA006, for example, 4-keto adipic acid - O - L-Ser; PMA007.1, for example, 4-keto adipic acid - O - D-Ser-D-His - succinyl CoA; PMA008, for example, 2-ketoglutaric acid - O - D-Ser-D-His; PMA009, for example, 2-ketoglutaric acid - D-Ala-D-His; PMA010.1, for example, 4-keto adipic acid - D-Ala-D-His; PMA011, for example, methylmalonic acid - O - D-Ser-D-His; PMA012, for example, methylmalonic acid - D-Ala-D-His; PMA013, for example, adipic acid - D-Ala-D-Ser-D-His; PMA014, for example, adipic acid - D-Ser-D-His; PMA019, for example, methylmalonic acid - D-Leu-D-His; and PMA020, for example, methylmalonic acid - D-Lys-D-His, and is selected from these.

15. ​ ​ The method according to any one of claims 1 to 9, wherein the compound is PMA010 (adipic acid - D - Ala - D - His).

16. The method according to any one of claims 1 to 9, wherein the compound is PMA007 (adipic acid - O - D - Ser - D - His).

17. The method according to any one of claims 1 to 9, wherein the compound is PMA011 (methylmalonic acid - D - Ala - D - His).

18. The method according to any one of claims 1 to 9, wherein the compound is PMA019 (methylmalonic acid - D - Leu - D - His).

19. The method according to any one of claims 1 to 9, wherein the compound is PMA020 (methylmalonic acid - D - Lys - D - His).

20. The method according to any one of claims 1 to 11, wherein the patient has propionic academia and A is methylmalonic acid excluding propionogenic amino acids or fatty acids.

21. The method according to claim 20, wherein the patient does not have methylmalonic academia.

22. The method according to any one of claims 1 to 21, wherein the patient has propionic academia or methylmalonic academia, and the method further comprises administering to the patient an inhibitor that blocks the formation of propionyl - CoA or methylmalonyl - CoA.

23. The method according to claim 22, wherein the inhibitor that blocks the formation of propionyl - CoA acid or methylmalonyl - CoA is 2,2 - dimethylbutyric acid or sodium 2,2 - dimethylbutyrate.

24. The method according to any one of claims 1 to 21, further comprising administering to the patient an inhibitor that restricts propionyl - CoA or methylmalonyl - CoA production from various sources, for example, co - administering as adjuvant therapy to the patient.

25. The method according to claim 24, wherein the inhibitor is an inhibitor of propionyl - CoA formation such as HST5040.

26. Structure A - B or B - A': [In the structure, A is a dicarboxylic acid, tricarboxylic acid, or a linear or branched fatty acid moiety selected from adipic acid, 3-hydroxy-adipic acid, 3-ketoadipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, α-ketoglutaric acid, oxaloacetic acid, heptanoic acid, 2,6-dimethylheptanoic acid, 4,8-dimethyldecanoic acid, 6-amino-2,4-dimethylheptanoic acid, linear fatty acid, or branched fatty acid and comprises: A' is a linear or branched fatty acid moiety selected from 6-hydroxy-hexanoic acid (hydroxyl group linked to B carboxylic acid as an ester bond), 6-amino-hexanoic acid (linked to B carboxylic acid via an amide bond), or 6-amino-2,4-dimethylheptanoic acid (linked to B carboxylic acid via an amide bond) and comprises: B is an amino acid, D-dipeptide of an amino acid, or D-tripeptide selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond, or linked to A' by an ester bond or an amide bond and comprises at least one amino acid. A compound having the same, or a pharmaceutically acceptable salt thereof.

27. Structure A-B: [In the structure, A is a structure containing an adipic acid moiety or a methylmalonic acid moiety; B is a D-amino acid, D-dipeptide of a D-amino acid, or D-tripeptide selected from D-Ser, D-Ala, D-Lys, D-Leu, and D-His, which is linked to A by an amide bond, or in the case of D-Ser, by an amide bond or an ester bond and comprises at least one amino acid. The compound according to claim 26 having the same, or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 26, wherein B comprises one or more of D-Ser, D-Ala, D-Lys, D-Leu, and / or D-His.

29. B is selected from -D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-Ser-D-His-DAla, -D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-Ser-D-His, -D-Ala-D-Ser, or -D-Ala-D-His, wherein D-Ser is linked by an amide bond (-N-bond) or an ester bond (-O-bond), the compound according to claim 28.

30. Structure: 【Chemical Formula 3】 [In the structure, R １ and R ２ are each independently oxygen connected by H, hydroxyl, or a double bond to form a keto moiety, where at least one of R １ and R ２ is H, and R ３ is linked via an ester bond (—O— bond) or an amide bond (—N— bond) and comprises 1 to 3 D-amino acids selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, and D-Val, or is one of —D-Ser, —O—D-Ser, —D-Ala, —D-His, —D-His—D-Ala—D-Ser, —D-His—D-Ala—O—D-Ser, —D-His—D-Ser—D-Ala, —D-His—O—D-Ser—D-Ala, —D-Ser—D-His—D-Ala, —O—D-Ser—D-His—D-Ala, —D-Ser—D-Ala—D-His, —O—D-Ser—D-Ala—D-His, —D-Ala—D-Ser—D-His, —D-Ala—O—D-Ser—D-His, —D-Ala—D-His—D-Ser, —D-Ala—D-His—D-Ser, —D-His—D-Ala, —D-His—D-Ser, —D-His—O—D-Ser, —D-Ser—D-His, —D-Ala—O—D-Ser, or —D-Ala—D-His] The compound according to claim 26, having

31. Structure: 【Chemical Formula 4】 [In the structure, R ５ is linked via an ester bond (-O-bond) or an amide bond (-N-bond) and comprises 1 to 3 D-amino acids selected from D-Ser, -O-D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, and D-Val, or is one of -D-Ser, -O-D-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-O-D-Ser, -D-His-D-Ser-D-Ala, -D-His-O-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -O-D-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -O-D-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-O-D-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-O-D-Ser, -D-Ser-D-His, -O-D-Ser-D-His-D-Ser-D-Ala, -O-D-Ser-D-Ala-D-Ala-D-Ser, -D-Ala-O-D-Ser, -D-Ala-D-His, -D-Leu-D-His, or -D-Lys-D-His] The compound according to claim 26, having

32. PMA001, for example, 4-hydroxyl adipic acid - O - D-Ser; PMA002, for example, 4-hydroxyl adipic acid - O - D-Ser-D-Ala; PMA003, for example, 4-hydroxyl adipic acid - O - D-Ser-D-Ala; PMA004, for example, 2-ketoglutaric acid - D-2-hydroxyglycine - D-Ala; PMA005, for example, 2-ketoglutaric acid - O - D-Ser-D-Ala; PMA006, for example, 4-keto adipic acid - O - L-Ser; PMA007.1, for example, 4-keto adipic acid - O - D-Ser-D-His - succinyl CoA; PMA008, for example, 2-ketoglutaric acid - O - D-Ser-D-His; PMA009, for example, 2-ketoglutaric acid - D-Ala-D-His; PMA010.1, for example, 4-keto adipic acid - D-Ala-D-His; PMA011, for example, methylmalonic acid - O - D-Ser-D-His; PMA012, for example, methylmalonic acid - D-Ala-D-His; and PMA013, for example, adipic acid - D-Ala-D-Ser-D-His; PMA014, for example, adipic acid - D-Ser-D-His; PMA019, for example, methylmalonic acid - D-Leu-D-His; and PMA020, for example, methylmalonic acid - D-Lys-D-His, the compound according to claim 26.

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