Fatty acid-d-amino acid peptide conjugates as back-up compounds for treatment of propionemia, methylmalonuria and energy metabolism disorders

Abstract

Provided herein are methods of providing a rejuvenation compound to a patient in need thereof. The methods may be used to treat propionemia, methylmalonuria, or fatty acid oxidation disorders in a patient. Also provided herein are compounds useful in those methods, comprising an adipic acid or methylmalonic moiety linked to one to three amino acids, such as D-amino acids, such as D-Ser, D-His, D-Lys, D-Leu, and / or D-Ala.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 394,136, filed on August 1, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0003] Statement Regarding Federal Funding

[0004] 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.

[0005] Provided herein are methods for treating propionic acidemia and methylmalonic aciduria, glutaric acidemia I and II, and fatty acid oxidation disorders. Also provided herein are compounds, compositions of matter specifically designed for treating propionic acidemia and methylmalonic aciduria and fatty acid oxidation disorders.

[0006] Disease conditions caused by succinyl-CoA deficiency include propionic acidemia (PA) (OMIM 606054); inborn errors of metabolism causing methylmalonic aciduria include those described in connection with OMIM 21000 (Behr syndrome), OMIM 609058 (methylmalonyl-CoA mutase), OMIM 613646 (transient methylmalonic aciduria due to cobalamin transporter receptor defect), OMIM 251100 (methylmalonic aciduria, cblA type), OMIM 251110 (methylmalonic aciduria, cblB type); glutaric acidemia I (GA1) OMIM 231670 and glutaric acidemia II or glutaric aciduria II (GA2) OMIM 231680; and fatty acid oxidation disorders including 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 any disorders that result in mitochondrial dysfunction that results in a decrease in mitochondrial ATP production.

[0007] Anaplerosis is the replenishment of catalytic intermediates carrying acetyl-CoA in the circulation when acetyl-CoA is oxidized. Major anaplerotic cellular substrates include pyruvate, glutamine / glutamate, aspartate / asparagine, and precursors of propionyl-CoA (odd-chain fatty acids, specific amino acids, C(5)-ketone bodies). Compounds, compositions, and treatment methods that can be used to replenish deficiencies in TCA cycle intermediates (such as succinyl-CoA deficiency) are expected.

[0008] Overview

[0009] According to one aspect or embodiment, provided herein is a method of providing a replenishing compound to a patient in need thereof, comprising administering to the patient a compound having the structure AB or B-A', wherein: A comprises a dicarboxylic acid, a tricarboxylic acid, or a linear or branched fatty acid moiety selected from: adipic acid, 3-hydroxyadipic 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, a linear fatty acid or a branched fatty acid; A' comprises a linear or branched fatty acid moiety selected from: 6-hydroxyhexanoic acid (the hydroxyl group is linked to the carboxylic acid B) B is an amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from the group consisting of 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 is linked to A' by an ester bond or an amide bond, or a pharmaceutically acceptable salt thereof.

[0010] According to one aspect or embodiment, provided herein is a method of treating a patient suffering from propionic acidemia (PA), methylmalonic aciduria (MMA), or a fatty acid oxidation disorder and having abnormally low amounts of anaplerotic intermediates, comprising administering to the patient a compound having structure AB or B-A', wherein:

[0011] a. For the treatment of PA, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, and α-ketoglutaric acid, A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from the group consisting of 6-hydroxyhexanoic acid and 6-aminohexanoic acid, and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, comprising at least one amino acid selected from the group consisting of D-Ser, D-Ala,

[0012] D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn or D-Leu, which is linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or linked to A′ via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof;

[0013] b. For the treatment of MMA, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, citric acid, isocitric acid, oxaloacetic acid and α-ketoglutaric acid; and A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from the group consisting of 6-hydroxyhexanoic acid or 6-aminohexanoic acid; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, comprising at least one amino acid selected from the group consisting of D-Ser, D-Ala, D-His,

[0014] D-Lys, D-Glu, D-Gln, D-Asp, D-Asn or D-Leu, which is linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or linked to A' via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof; or

[0015] c. For the treatment of fatty acid oxidation disorders, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain or branched fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid, heptanoic acid, 2,6-dimethylheptanoic acid,

[0016] 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, an even-numbered straight-chain fatty acid, or a branched-chain fatty acid; A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from: 6-hydroxyhexanoic acid,

[0017] 6-aminohexanoic acid or 6-amino-2,4-dimethylheptanoic acid; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from the group consisting of D-Ser,

[0018] 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 via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or is linked to A' via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof.

[0019] According to another aspect or embodiment, the present invention also provides a compound having a structure AB or B-A', wherein A includes a dicarboxylic acid, a tricarboxylic acid or a linear or branched fatty acid portion selected from: adipic acid, 3-hydroxyadipic 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, a linear fatty acid or a branched fatty acid; A' includes a linear or branched fatty acid portion selected from: 6-hydroxyhexanoic acid (the hydroxyl group is connected to the B carboxylic acid as an ester bond), 6-amino hexanoic acid (linked to B carboxylic acid through an amide bond) or 6-amino-2,4-dimethylheptanoic acid (linked to B carboxylic acid through an amide bond); and B is an amino acid, a D-dipeptide or a D-tripeptide of an amino acid, including at least one amino acid selected from the group consisting of 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, linked to A through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or linked to A' through an ester bond or an amide bond, or a pharmaceutically acceptable salt thereof.

[0020] The following numbered clauses summarize various aspects or embodiments of the invention:

[0021] Item 1. A method of providing a replenishing compound to a patient in need thereof, comprising administering to the patient a compound having the structure AB or B-A', wherein: A comprises a dicarboxylic acid, a tricarboxylic acid, or a linear or branched fatty acid moiety selected from: adipic acid, 3-hydroxyadipic 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, a linear fatty acid or a branched fatty acid; A' comprises a linear or branched fatty acid moiety selected from: 6-hydroxyhexanoic acid (the hydroxyl group is linked to the B carboxylic acid as an ester bond) ), 6-aminohexanoic acid (linked to B carboxylic acid through an amide bond) or 6-amino-2,4-dimethylheptanoic acid (linked to B carboxylic acid through an amide bond); and B is an amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from the following: 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 through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or is linked to A' through an ester bond or an amide bond, or a pharmaceutically acceptable salt thereof.

[0022] Item 2. The method described in Item 1, wherein the compound has structure AB, wherein: A includes an adipic acid portion or a methylmalonic acid portion; and B includes 1-3 D-amino acids selected from D-Ser, D-Ala, D-Lys, D-Leu or D-His, which are connected to A through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof, which is used to treat fatty acid oxidation disorders.

[0023] Item 3. The method of Item 1 or 2, wherein the anaplerotic product generated enters the Krebs cycle as an intermediate at various points, such as, for example, acetyl-CoA, citrate, isocitrate, α-ketoglutarate, succinyl-CoA and / or oxaloacetate.

[0024] Clause 4. A method of treating a patient suffering from propionic acidemia (PA), methylmalonic aciduria (MMA), or a fatty acid oxidation disorder and having abnormally low amounts of anaplerotic intermediates, comprising administering to the patient a compound having structure AB or BA', wherein:

[0025] a. For the treatment of PA, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, and α-ketoglutaric acid, A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from the group consisting of 6-hydroxyhexanoic acid and 6-aminohexanoic acid, and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, comprising at least one amino acid selected from the group consisting of D-Ser, D-Ala,

[0026] D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn or D-Leu, which is linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or linked to A′ via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof;

[0027] b. For the treatment of MMA, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, citric acid, isocitric acid, oxaloacetic acid and α-ketoglutaric acid; and A' comprises a straight even-numbered dicarboxylic acid or fatty acid moiety selected from the group consisting of 6-hydroxyhexanoic acid or 6-aminohexanoic acid; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, comprising at least one amino acid selected from the group consisting of D-Ser, D-Ala, D-His,

[0028] D-Lys, D-Glu, D-Gln, D-Asp, D-Asn or D-Leu, which is linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or linked to A' via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof; or

[0029] c. For the treatment of fatty acid oxidation disorders, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain or branched fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid, heptanoic acid, 2,6-dimethylheptanoic acid,

[0030] 4,8-dimethylnonanoic acid, 6-amino-2,4-dimethylheptanoic acid, an even-numbered straight-chain fatty acid, or a branched-chain fatty acid; A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from: 6-hydroxyhexanoic acid,

[0031] 6-aminohexanoic acid or 6-amino-2,4-dimethylheptanoic acid; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from the group consisting of D-Ser,

[0032] 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 via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or is linked to A' via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof.

[0033] Item 5. The method of Item 4, wherein the compound has structure AB, wherein: A includes an adipic acid moiety or a methylmalonic acid moiety (not used for MMA); and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from D-Ser, D-Ala, D-Lys, D-Leu and D-His, which is linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof, in an amount effective to normalize the level of anaplerotic intermediates.

[0034] Clause 6. The method of any one of clauses 1-5, wherein the patient has propionic acidemia (PA); transient methylmalonic aciduria (MMA) due to a defect in the cobalamin transporter receptor; methylmalonic aciduria, cblA type; methylmalonic aciduria, cblB type; 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 acidemia I (GA I or GA1); or glutaric acidemia II (GA I or GA2).

[0035] Clause 7. The method of any one of clauses 1-5, wherein the compound comprises Fig.17A and 17BThe moiety types listed in the table above, and the compounds are used to treat Fig.17A and 17B and, where relevant, optionally contraindicated in the treatment of Fig.17A and 17B The corresponding disease indicated in .

[0036] Clause 8. The method of any one of Clauses 1-7, wherein the patient has reduced succinyl-CoA or lysine succinylation.

[0037] Clause 9. The method of any one of clauses 1-5, wherein the patient has glutaric acidemia I (GA I or GA1), while glutaric acid or lysine are not included in the compound structure, or has glutaric acidemia II (GA 2 or GA II), while glutaric acid or lysine, fatty acids and branched chain amino acids are not included in the compound structure, and the fatty acids and branched chain amino acids require ETF or ETF dehydrogenase for their breakdown. GA II cannot have: Ile, Leu, Val, Lys, glutaric acid or adipic acid, branched or odd chain fatty acids, or any saturated fatty acids, C4 and higher.

[0038] Clause 10. The method of any one of clauses 1-9, wherein B comprises one or more of D-Ser, D-Ala, D-Lys, D-Leu and / or D-His.

[0039] Clause 11. The method of any of clauses 1-10, 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, wherein D-Ser is linked by an amide bond (-N-linked) or an ester bond (-O-linked).

[0040] Clause 12. The method according to any one of clauses 1 to 9, wherein the compound has the following structure:

[0041]

[0042] wherein R1 and R2 are independently H, hydroxyl, or oxygen linked by a double bond to form a ketone moiety, wherein at least one of R1 and R2 is H, and R3 is linked by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of 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 the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-OD-Ser, -D-His-D-Ser-D-Ala, -D-H is-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-Se r-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-OD-Ser, -D-Ser-D-His, -D-Ala-OD-Ser, or -D-Ala-D-His.

[0043] Clause 13. The method of any one of clauses 1 to 9, wherein the compound has the following structure:

[0044]

[0045] wherein R5 is linked by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of 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 the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-His-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D-Ser- D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-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-OD-Ser, -D-Ser-D-His, -OD-Ser-D-His-D-Ser-D-Ala, -OD-Ser-D-Ala, -D-Ala-D-Ser, -D-Ala-OD-Ser, -D-Ala-D-His, -D-Leu-D-His, or -D-Lys-D-His.

[0046] Clause 14. The method of any one of clauses 1-9, wherein the compound is selected from: PMA001, for example, 4-hydroxyadipate-OD-Ser; PMA002, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA003, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA004, for example, 2-ketoglutarate-D-2-hydroxyglycine-D-Ala; PMA005, for example, 2-ketoglutarate-OD-Ser-D-Ala; PMA006, for example, 4-ketoadipate-OL-Ser; PMA007.1, for example, 4-ketoadipate-OD-Ser-D-His; PMA008, for example, 2-ketoglutarate-D-2-hydroxyglycine-D-Ala. glutarate-OD-Ser-D-His; PMA009, for example, 2-ketoglutarate-D-Ala-D-His; PMA010.1, for example, 4-ketoadipate-D-Ala-D-His; PMA011, for example, methylmalonate-OD-Ser-D-His; PMA012, for example, methylmalonate-D-Ala-D-His; PMA013, for example, adipate-D-Ala-D-Ser-D-His; PMA014, for example, adipate-D-Ser-D-His; PMA019, for example, methylmalonate-D-Leu-D-His; and PMA020, for example, methylmalonate-D-Lys-D-His.

[0047] Clause 15. The method of any one of Clauses 1-9, wherein the compound is PMA010 (adipic acid-D-Ala-D-His).

[0048] Clause 16. The method of any one of clauses 1-9, wherein the compound is PMA007 (adipic acid-OD-Ser-D-His).

[0049] Clause 17. The method of any one of clauses 1-9, wherein the compound is PMA011 (methylmalonic acid-D-Ala-D-His), not for MMA.

[0050] Clause 18. The method of any one of clauses 1-9, wherein the compound is PMA019 (methylmalonic acid-D-Leu-D-His), not for MMA.

[0051] Clause 19. The method of any one of clauses 1-9, wherein the compound is PMA020 (methylmalonic acid-D-Lys-D-His), not for MMA.

[0052] Clause 20. The method of any one of clauses 1-11, wherein the patient has propionic acidemia, and wherein A is methylmalonic acid, excluding propiogenic amino acids or fatty acids.

[0053] Clause 21. The method of Clause 20, wherein the patient does not have methylmalonic aciduria, excluding methylmalonic acid.

[0054] Clause 22. The method of any one of Clauses 1-21, wherein the patient has propionic acidemia or methylmalonic aciduria, and the method further comprises administering to the patient an inhibitor that blocks the formation of propionyl-CoA or methylmalonyl-CoA.

[0055] Clause 23. The method of Clause 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.

[0056] Clause 24. The method of any of Clauses 1-21, further comprising administering to the patient (eg, co-administering to the patient as an adjunct therapy) an inhibitor that limits the production of propionyl-CoA or methylmalonyl-CoA from various sources.

[0057] Clause 25. The method of Clause 24, wherein the inhibitor is an inhibitor of propionyl-CoA or methylmalonyl-CoA formation, such as HST5040.

[0058] Item 26. A compound having the structure AB or B-A', wherein A comprises a dicarboxylic acid, a tricarboxylic acid or a linear or branched fatty acid moiety selected from: adipic acid, 3-hydroxyadipic 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, a linear fatty acid or a branched fatty acid; A' comprises a linear or branched fatty acid moiety selected from: 6-hydroxyhexanoic acid (the hydroxyl group is linked to the B carboxylic acid as an ester bond), 6-aminohexanoic acid (via an acyl group), and B is an amino acid, a D-dipeptide or a D-tripeptide of an amino acid, including at least one amino acid selected from the group consisting of 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 through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or is linked to A' through an ester bond or an amide bond, or a pharmaceutically acceptable salt thereof.

[0059] Clause 27. The compound described in Clause 26, wherein the compound has structure AB, wherein: A includes an adipic acid moiety or a methylmalonic acid moiety; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from D-Ser, D-Ala, D-Lys, D-Leu and D-His, which is connected to A through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof.

[0060] Clause 28. The compound of Clause 26, wherein B comprises one or more of D-Ser, D-Ala, D-Lys, D-Leu and / or D-His.

[0061] Clause 29. The compound of Clause 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, wherein D-Ser is linked via an amide bond (-N-linked) or an ester bond (-O-linked).

[0062] Item 30. The compound of Item 26, which has the following structure:

[0063]

[0064] wherein R1 and R2 are independently H, hydroxyl or oxygen connected by a double bond to form a ketone moiety, wherein at least one of R1 and R2 is H, and R3 is connected by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of 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 the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-OD-Ser, -D-His-D-Ser-D-Ala, -D-H is-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-Se r-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-OD-Ser, -D-Ser-D-His, -D-Ala-OD-Ser, or -D-Ala-D-His.

[0065] Item 31. The compound of Item 26, which has the following structure:

[0066]

[0067] wherein R5 is linked by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of D-Ser, -OD-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, and D-Val, or is one of the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-His-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D- Ser-D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-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-OD-Ser, -D-Ser-D-His, -OD-Ser-D-His-D-Ser-D-Ala, -OD-Ser-D-Ala-D-Ala-D-Ser, -D-Ala-OD-Ser, -D-Ala-D-His, -D-Leu-D-His, or -D-Lys-D-His.

[0068] Clause 32. The compound of clause 25, which is selected from: PMA001, for example, 4-hydroxyadipate-OD-Ser; PMA002, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA003, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA004, for example, 2-ketoglutarate-D-2-hydroxyglycine-D-Ala; PMA005, for example, 2-ketoglutarate-OD-Ser-D-Ala; PMA006, for example, 4-ketoadipate-OL-Ser; PMA007.1, for example, 4-ketoadipate-OD-Ser-D-His-succinyl-CoA; PMA008, for example, 2-ketoglutarate-D-2-hydroxyglycine-D-Ala. Acid-OD-Ser-D-His; PMA009, for example, 2-ketoglutarate-D-Ala-D-His; PMA010.1, for example, 4-ketoadipate-D-Ala-D-His; PMA011, for example, methylmalonic acid-OD-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.

[0069] BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figures 1A-1C Exemplary compounds as described herein are provided wherein the fatty acyl moiety and the D-amino acid, dipeptide or oligopeptide moiety are different. Figure 1A Exemplary compounds are provided of a dicarboxylic acid linked to a D-amino acid via an ester bond provided by the hydroxyl oxygen of D-serine, and wherein the dicarboxylic acid is a hydroxy- or keto-substituted dicarboxylic acid. Figure 1B Exemplary compounds of dicarboxylic acids linked to D-amino acids through amide bonds are provided. Figure 1C Exemplary compounds of fatty acids (R) linked to D-amino acids, dipeptides or oligopeptides via amide bonds are provided, which are useful for treating pyruvate dehydrogenase deficiency. Figure 1CIn PMA015.x, PMA016.x, PMA017.x, PMA018.x, PMA019.x and PMA020.x, x can be an integer from 1 to 8, wherein: when x is 1, R is adipoyl; when x is 2, R is glutaryl; when x is 3, R is succinyl; when x is 4, R is methylmalonyl; when x is 5, R is heptanoyl; when x is 6, R is 2,6-dimethylheptanoyl; when x is 7, R is 4,8-dimethylheptanoyl; and when x is 8, R is 6-amino-2,4-dimethylheptanoyl.

[0071] Figure 2 is a schematic diagram of the Krebs cycle (also known as the TCA or citric acid cycle) showing disorders that lead to depletion of intermediates of the cycle. Amino acids with significant contributions as anaplerotic are depicted. Abbreviations of disorders mentioned: FAOD, fatty acid oxidation disorders; MADD, multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria II, GA2, caused by ETF or ETF dehydrogenase deficiency); PA, propionic acidemia; MMA, methylmalonic aciduria; PDHD, pyruvate dehydrogenase deficiency; SUCLA2D, succinyl-CoA synthetase (SUCLA2) deficiency; FD, fumarase deficiency; MDH2, mitochondrial malate dehydrogenase deficiency.

[0072] Figure 3 Figure 1 is a schematic diagram of the propionyl-CoA metabolic pathway illustrating its role as the major source of succinyl-CoA and the role of succinyl-CoA in cellular physiology. Propionogenic amino acids have been estimated to account for 46% ± 21 of total propionate production in PA patients. Propionate produced by intestinal bacteria is estimated to account for 22% ± 9 of that in the circulation, and ~30% is attributed to fatty acid sources. The physiological role of succinyl-CoA is complex, with a role in lysine succinylation of hundreds of mitochondrial and cellular proteins, and therefore, the function of these mitochondrial and cellular proteins is greatly affected by succinyl-CoA depletion in PA patients and other metabolic disorders.

[0073] Figure 4 It was shown that five known enzymes specifically catalyze the first step of the pathway with overlapping substrate chain lengths. The remaining pathway reactions are carried out by the trifunctional protein heterooctamer TFP, which performs three different reactions to complete the cycle. Cycle output products include acetyl-CoA, which enters the TCA cycle, and propionyl-CoA, which is converted to succinyl-CoA.

[0074] Figure 5The structures of the compounds encoded as follows are depicted: PMA007 (adipic acid-OD-Ser-D-His; 6-((R)-2-amino-3-(((S)-1-carboxy-2-(1H-imidazol-4-yl)ethyl)amino)-3-oxopropoxy)-6-oxohexanoic acid, as described herein) and PMA010 (adipic acid-D-Ala-D-His; 6-(((R)-1-(((R)-1-carboxy-2-(1H-imidazol-4-yl)ethyl)amino)-1-oxopropan-2-yl)amino)-6-oxohexanoic acid, as described herein).

[0075] Figure 6 The structures of the compounds coded as follows are depicted: PMA011 (methylmalonic acid-D-Ala-D-His; 3-(((R)-1-(((R)-1-carboxy-2-(1H-imidazol-4-yl)ethyl)amino)-1-oxopropan-2-yl)amino)-2-methyl-3-oxopropanoic acid, as described herein); PMA019 (methylmalonic acid-D-Leu-D-His; 3-(((R)-1-(((R)-1-carboxy-2-(1H-imidazol-4-yl)ethyl)amino)-1-oxopropan-2-yl)amino)-2-methyl-3-oxopropanoic acid; -(((R)-6-amino-1-(((R)-1-carboxy-2-(1H-imidazol-4-yl)ethyl)amino)-4-methyl-1-oxopentan-2-yl)amino)-2-methyl-3-oxopropanoic acid, as described herein); and PMA020 (methylmalonic acid-D-Lys-D-His; 3-(((R)-6-amino-1-(((R)-1-carboxy-2-(1H-imidazol-4-yl)ethyl)amino)-1-oxohexan-2-yl)amino)-2-methyl-3-oxopropanoic acid, as described herein).

[0076] Figure 7 Immunocytochemical micrographs showing the effect of incubation of Fb859 propionic acidemia patient fibroblasts with 90 μM PMA010, 90 μM PMA011, 90 μM succinate, 90 μM methylmalonic acid, or 90 μM adipic acid for 72 hours on lysine succinylation. Fibroblasts were immunocytochemically stained with anti-succinyllysine antibody, anti-MTCO1 antibody, and DAPI staining for nuclei. Instrument: Zeiss LSM 710 confocal microscope. Magnification: 40x. Cells were stained at 3-5x 10 4 Cells were grown in glass coverslips at a seeding density of 100 cells / mL. The culture medium used for untreated and treated groups did not have glucose, glutamine, or pyruvate and contained lipid-stripped FBS instead of regular FBS. Scale bar = 20 μm.

[0077] Figures 8A-8F is unprocessed ( Fig. 8A ) and 30 μM and 90 μM D-serine ( Figure 8B ), 30μM and 90μM PMA007 ( Figure 8C ) or 30 μM and 90 μM PMA010 ( Fig.8D Comparison of lysine succinylation of cellular proteins visualized by immunofluorescence confocal microscopy in patients with propionic acidemia (Fb859) treated with . Scale bar = 20 μm. Fig. 8E is a bar graph showing the response to D-serine and PMA007 treatment, from Figure 8B and 8C Quantification of the percent change in lysine succinylation (green) signal in immunofluorescence confocal micrographs. Fig.8F is a bar graph showing the responses to D-serine and PMA010 treatments from the D-serine replicate experiment and Fig.8D Quantification of the percentage change of lysine succinylation (green) signal in immunofluorescence confocal micrographs of . Asterisks indicate statistical significance calculated at the raw data level (n=3); **P<0.01, ***P<0.001, ****P<0.0001 statistically compared to untreated. T-test was used for statistical analysis.

[0078] Figures 9A-9F Human HEK293 control and untreated ( Fig.9A and 9B ) and 30 μM and 90 μM PMA007 ( Fig. 9C ) or 30 μM and 90 μM PMA010 ( Fig.9D HEK293 PCCA treated with - / - Comparison of lysine succinylation of cellular proteins in cells visualized by immunofluorescence confocal microscopy. Fig. 9B , 9C Cells in 9D and 9D were grown in medium without glucose, pyruvate, and glutamine. Scale bar = 20 μm. Fig.9E is a bar graph showing the response to PMA007 treatment, from Fig. 9B and 9C Quantification of the percent change in lysine succinylation (green) signal in immunofluorescence confocal micrographs. Fig.9F is a bar graph showing the response to PMA010 treatment, from Fig. 9B and Fig.9D Quantification of the percentage change of lysine succinylation (green) signal in immunofluorescence confocal micrographs of . Asterisks indicate statistical significance calculated at the raw data level (n=3); **P<0.01, ****P<0.0001 in statistical comparison with untreated. T-test was used for statistical analysis.

[0079] Fig.10is a Western blot showing the reduction of specific signals of various ETC components in the control Fb826 control normal levels and in the propionic acidemia (PA) cell lines Fb859 and Fb900 and the methylmalonic aciduria (MMA) cell line Fb857 compared to the control Fb826.

[0080] Fig.11 is a Western blot showing correction of the signals of complex III subunit core 2 48-kDa (UQCRC2), complex IV subunit II 22-kDa (COXII), and complex I subunit NDUFB8 18-kDa, which was most prominent in the propionic acidemia (PA) cell line Fb859 compared to the methylmalonic aciduria (MMA) cell line Fb857.

[0081] Figures 12A-12E is a graph showing the effect of anaplerotic compound treatment on mitochondrial energetics and detection of free radical oxygen species ROS. Figures 12A-12D is a graph showing changes in oxygen consumption rate (OCR) parameters after addition of OXPHOS inhibitors to the culture medium of PA patient cells Fb859 treated with 30 μM and 90 μM of PMA007, PMA010, or individual components of D-serine, D-histidine, or adipic acid for 72 hours. Fig.12E Figure 3 shows ROS detected using MitoSOX Red as a superoxide indicator probe in cells grown in medium containing PMA007 or PMA010 or adipic acid, D-His, and D-Ser. 5 Cell suspensions of 10 cells / mL were seeded in 96-well plates and treated with the compounds for 72 hours. The cells were washed and incubated with 5 μM (MitoSOX Red; Invitrogen) for 15 minutes at 37°C, % 5% CO2 for superoxide generation measurement. After incubation, the cells were washed, fresh culture medium was added, and fluorescence was measured using a microplate reader set to 520 nm excitation and 580 nm emission.

[0082] Figures 13A-13H is to show the response to different concentrations of PMA010 ( Figures 13A-13D ) or PMA011( Figures 13E-13H ) Graph showing changes in oxygen consumption rate parameters of PA patient cells Fb859 treated with . Values ​​are plotted as percentages relative to untreated. Asterisks indicate statistical significance calculated at the raw data level (n=6-8); *P<0.1, **P<0.01, ***P<0.001, ****P<0.0001 in statistical comparison with untreated. T-test was used for statistical analysis.

[0083] Figures 14A-14DThe results show that FB859 patients and HEK293 PCCA cells treated with PMA007 or PMA010 for 72 hours - / - Figure Quantification of propionyl-CoA replacement metabolites secreted from the culture medium of cultured cells: propionylcarnitine (C3-carnitine; Fig.14A ), propionylglycine (C3-glycine; Fig. 14B ), hydroxypropionylcarnitine (C3OH-carnitine; Fig. 14C ) and hydroxypropionylglycine (C3OH-glycine, Fig.14D ). Data are presented as percentages relative to untreated cells. In the culture medium of Fb859 cells treated with a control (Cntl, 0 μM) of glucose and pyruvate, the culture medium propionylcarnitine was 0.17 μM, whereas in the untreated control (which had no glucose or pyruvate and contained stripped FBS (fat-free) in the culture medium), propionylcarnitine was 0.433 μM.

[0084] Figures 15A-15D is a graph showing measurement of mitochondrial reactive oxygen species (ROS) production using MitoSOX Red as a superoxide indicator probe. Fig.15A is a graph showing a control fibroblast cell line FB826 treated with PMA010, PMA011, PMA019 and PMA020. Fig. 15B is a graph showing the fibroblast cell line Fb859 from a propionic acidemia (PA) patient treated with PMA010, PMA011, PMA019, and PMA020. Fig. 15C is a graph showing the fibroblast cell line Fb900 from a patient with propionic acidemia (PA) treated with PMA010, PMA011, PMA019, and PMA020. Fig.15D is a graph comparing the levels of ROS production in a control fibroblast cell line (FB826), a PA fibroblast cell line (Fb900), and a glutaric acidemia II (GA II) patient fibroblast cell line (Fb930, Fb961) in response to treatment with PMA011. The data are the average of readings from 3 replicate wells.

[0085] Fig.16 are immunocytochemical micrographs showing lysine hyposuccinylation in fatty acid oxidation disorder cell lines using anti-succinyllysine, anti-MTCO1 antibodies and DAPI for nuclei, as observed in defective cells (as indicated). Instrument: Zeiss LSM 710 confocal microscope. Magnification: 40x.

[0086] Fig.17A and 17B is a table showing the functional contribution of this class of compounds as potential parts of anaplerosis as well as the mode of action and catabolic pathways.

[0087] Details

[0088] Unless otherwise expressly stated, the use of numerical values ​​in the various ranges specified in this application are expressed as approximate values, just as the minimum and maximum values ​​in the ranges are preceded by the word "about". In this way, slight variations above and below the ranges can be used to achieve substantially the same results as the values ​​in the ranges. In addition, unless otherwise stated, the disclosure of ranges 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 (one or more).

[0089] As used herein, the term "comprising" is open ended and may 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 feature(s). The term "consisting of" excludes any elements, steps, or ingredients not specified in the claim. As used herein, embodiments "comprising" one or more of the described elements or steps also include, but are not limited to, embodiments "consisting essentially of" and "consisting of" the described elements or steps.

[0090] As used herein, the term "patient" or "subject" refers to members of the animal kingdom, including, but not limited to, humans, and "mammal" refers to all mammals, including, but not limited to, humans.

[0091] Provided herein are compounds and methods for treating certain metabolic diseases that include, as a symptom or sequelae, or are caused by a deficiency in one or more anaplerotic reactions or pathways that produce anaplerotic compounds in a patient. Such diseases include, for example and without limitation, propionic acidemia, methylmalonic acidemia, fatty acid oxidation (e.g., beta oxidation) disorders, or specific Krebs cycle ( Figure 2 )-related enzyme deficiencies, such as pyruvate dehydrogenase deficiency (see Fig.17A and 17B). Compounds useful in the methods described herein comprise an adipic acid or methylmalonic acid moiety linked by an amide bond to a single D amino acid, D-dipeptide or D-tripeptide consisting of the D amino acid forms of 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). In the presence of Ser, it may be linked by its R group O to form an ester, or by its amine group to form a standard peptide bond. Further descriptions of the various compounds are provided below. When administered to a patient, the compound is broken down into its components, which supplement the anaplerotic reactions and pathways in the patient, and thus address the causes, symptoms or sequelae of certain diseases. Since different metabolic diseases result in the lack of different anaplerotic compounds, different compounds may be selected to support patients with different diseases.

[0092] It should be understood that different patients' metabolic pathways may break down compounds in different ways, depending on factors such as patient genetics, nutrition, health status, and activity. That is, it is expected that the compound is primarily metabolized into intermediates that replenish certain anaplerotic compounds produced by the anaplerotic pathway in a given patient. For example, adipic acid derivatives (i.e., adipic acid or its derivatives, such as described herein) are expected to primarily provide one acetyl-CoA and one succinyl-CoA in a patient. Methylmalonic acid is expected to replenish succinyl-CoA in a patient. D-amino acids are included in the structure because they are not directly used in protein synthesis or structure, but are metabolized to their deaminated form. D-His is expected to increase α-ketoglutarate levels and therefore serve as a succinyl-CoA precursor in the TCA cycle. D-Ala is expected to undergo deamination to form pyruvate, which can be broken down by pyruvate dehydrogenase for use in the TCA cycle, carboxylated to oxaloacetate (see Figure 2 ), or can be used in gluconeogenesis. D-Ser can be deaminated and / or can be broken down to form pyruvate or glycine, or it can enter other pathways. Although all amino acids can be deaminated to the keto form and then reaminated to the L-form, the loss of the L-form for proteins and other anabolic pathways should not significantly affect the bulk of other substances that are degraded.

[0093] As used herein, the term "treating" or "treatment" may refer to a beneficial or specific outcome, such as improving one or more functions or symptoms of a disease. The term "treating" or "treatment" may also include, but is not limited to, alleviation or improvement of one or more symptoms of propionic acidemia, methylmalonic acidemia, or fatty acid oxidation (e.g., β-oxidation) disorders or normalization of clinically relevant markers. "Treatment" may also refer to prolonging survival compared to the expected survival in the absence of treatment. As used herein, "transdermal" means "through the skin."

[0094] In the context of disease markers or symptoms, "lower" can refer to a clinically relevant and / or statistically significant reduction of such a level. For example, the reduction can be at least 10%, at least 20%, at least 30%, at least 40% or more, down to a level accepted within a normal range for individuals without such an obstacle, or down to a detection level below the assay. The reduction can be down to a level accepted within a normal range for individuals without such an obstacle, which can also be referred to as the normalization of the level. The reduction can be the normalization of the level of the signs or symptoms of the disease, i.e., the reduction of the difference between the subject level of the disease sign and the normal level of the disease sign (e.g., when the subject's value must be reduced to reach a normal value, the normal upper limit level is reached, and when the subject's value must be increased to reach a normal level, the normal lower limit level is reached). Methods described herein can include the clinically relevant reduction of any symptom of a disease (e.g., as described herein) or the normalization of clinical marker levels.

[0095] As used herein, a "therapeutically effective amount" may include an amount of a compound as described herein that, when administered to a subject suffering from a disease, may be sufficient to achieve treatment of the disease (e.g., by reducing, ameliorating, or maintaining an existing disease or one or more symptoms of the disease, including normalizing any relevant clinical markers). A "therapeutically effective amount" may vary depending on how the composition is administered, the disease and its severity and history, age, weight, family history, genetic makeup, type of previous or concurrent treatment (if any), and other individual characteristics of the subject to be treated.

[0096] A "therapeutically effective amount" may also include an amount of an agent that produces a local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. The compounds described herein may be administered in an amount sufficient to produce a reasonable benefit / risk ratio applicable to such treatment.

[0097] As used herein, the phrase "pharmaceutically acceptable carrier" may refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate or stearic acid), or solvent encapsulating material, used to carry or transport the compound of interest from one organ or part of the body to another. Each carrier may be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not deleterious to the subject being treated. Some non-limiting examples of materials that may serve 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 carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) lubricants, such as magnesium stearate; (8) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (9) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (10) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (11) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (12) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (13) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (14) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (15) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (16) cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose state), 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 glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffered 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 nontoxic compatible substances used in pharmaceutical formulations.

[0098] Pharmaceutically acceptable salts of any compound described herein may also be used in the methods described herein. Pharmaceutically acceptable salt forms of the compounds described herein may be prepared by conventional methods known in the pharmaceutical art, and include veterinarily acceptable salts as a class. For example and without limitation, where the compound contains a carboxylic acid group, a suitable salt thereof may be formed by reacting the compound with an appropriate base to provide a 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 ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine, and N-methylglutamine.

[0099] Non-limiting examples of pharmaceutically acceptable base salts include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and 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, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-reduced glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris-(hydroxymethyl)-methylamine (tromethamine).

[0100] Non-limiting examples of pharmaceutically acceptable acid salts include acetate, adipate, alginate, arginine, aspartate, benzoate, besylate (benzenesulfonate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, galacterate, galacturonic acid salt, glucoheptonate, 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, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, and phthalate.

[0101] Multiple salt forms are also considered pharmaceutically acceptable salts. Common, non-limiting examples of multiple salt forms include: bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride.

[0102] Therefore, as used herein, "pharmaceutically acceptable salt" is intended to refer to an active ingredient (drug) comprising a salt form of any compound as described herein. The salt form may impart improved and / or desired pharmacokinetic / pharmacodynamic properties to the compounds described herein.

[0103] An organic compound can form a complex with a solvent in which the organic compound reacts or precipitates or crystallizes from the solvent. These complexes are referred to as "solvates". Complexes with water are referred to as "hydrates". Solvates of compounds disclosed herein (e.g., compound AB or B-A') are considered. Organic chemists will also understand that many organic compounds can exist in more than one crystalline form. For example, a crystalline form may vary from solvate to solvate. Therefore, all crystalline forms of compounds described herein (e.g., compound AB or B-A') or pharmaceutically acceptable solvates thereof are within the scope of the present invention (in general, see AM Healy et al., Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals, Adv. Drug Deliv. Rev. August 1, 2017; 117: 25-46).

[0104] A "group" or "functional group" is a portion of a larger molecule that comprises or consists of a group of atoms and / or bonds that impart chemical or physical properties to the molecule. A "residue" is a portion of a compound or monomer, such as the following in the context of the present disclosure: adipic acid, 3-hydroxyadipic 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-hydroxyhexanoic acid, 6-aminohexanoic 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, which portion of the compound or monomer remains in the larger molecule (such as a polymer chain or macromolecule described herein) after the compound or monomer is introduced into the larger molecule. Compounds that contain the residue of another smaller compound (e.g., adipic acid, methylmalonic acid, D-Ser, D-Ala, D-Leu, D-Lys, and D-His) are considered to contain that compound. A "moiety" is a portion of a molecule and may contain one or more functional groups, and in the case of an "active moiety," may be a characteristic portion of a molecule or compound that confers activity (e.g., pharmacological activity or physiological activity) to the molecule, as contrasted with an inactive portion of the molecule (e.g., an ester of the active moiety or a salt of the active agent).

[0105] Provided herein are compounds that can be used to treat propionic acidemia, methylmalonic aciduria, and fatty acid oxidation disorders. The compounds may be referred to as anaplerotic compounds or anaplerotic agents because of their utility in anaplerotic therapy, for example, to replenish or supplement metabolic intermediates that may be reduced in patients with metabolic diseases such as propionic acidemia, methylmalonic aciduria, or fatty acid oxidation disorders. The metabolic intermediates may be succinyl-CoA or other intermediates. For example, the demand for α-ketoglutarate and succinyl-CoA for a variety of biochemical functions makes it desirable to replenish the latter from other sources, including amino acid metabolism and branched and odd-chain fatty acids. The compound has the structure AB or B-A', wherein "A" is a dicarboxylic acid, a tricarboxylic acid, or a linear or branched fatty acid selected from: adipic acid, 3-hydroxyadipic 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, a linear fatty acid or a branched fatty acid, and "A'" is a linear or branched fatty acid portion selected from: 6-hydroxyhexanoic acid, 6-aminohexanoic acid or 6-amino-2,4-dimethylheptanoic acid.

[0106] "Adipic acid" is a substituted or unsubstituted straight-chain aliphatic dicarboxylic acid having a total of six carbon atoms. For example, adipic acid can be substituted with a hydroxyl group on the third carbon atom to form 3-hydroxyadipic acid, or can be substituted with a ketone on 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 can be substituted with a hydroxyl group on the second carbon atom to form α-hydroxyglutaric acid, or can be substituted with a ketone on 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 can be substituted with a hydroxyl group on the second carbon atom to form 2-hydroxysuccinic acid, or can be substituted with a ketone on the second carbon atom to form 2-ketosuccinic acid. "Citric acid" is a substituted or unsubstituted tricarboxylic acid with a hydroxyl substituent on the second carbon atom. For example, citric acid can be additionally substituted with a hydroxyl group to form hydroxycitric acid.

[0107] In one aspect or embodiment, the compound has structure AB, and "A" includes an adipic acid moiety or a methylmalonic acid moiety combined with "B", "B" is an amino acid, a D-dipeptide or a D-tripeptide of an amino acid, including at least one amino acid selected from the group consisting of 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). A "D-amino acid" is an amino acid in which the stereoisomeric carbon alpha of the amino group has a D-configuration. A "D-dipeptide" is a peptide consisting of two D-amino acid residues. A "D-tripeptide" is a peptide consisting of three D-amino acid residues. In one aspect or embodiment, "B" is or includes 1-3 amino acids selected from D-Ser, D-Ala, D-Lys, D-Leu and / or D-His. Alternatively, "B" is or includes -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, wherein D-Ser may be linked via an amide bond (-N-linked) or an ester bond (-O-linked). Other alternatives are D-Leu and / or D-Lys, which may replace D-Ala or D-Ser.

[0108] In the compound structure AB, 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, wherein 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 with 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, wherein 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 like their L-counterparts, and therefore, D-amino acids undergo conversion to anaplerotic compounds, which may be depleted in patients with metabolic diseases such as propionic acidemia, methylmalonic aciduria, or fatty acid oxidation disorders.

[0109] Some exemplary useful fatty acids for A and A' include linear or branched, saturated or unsaturated C 4-24 Fatty acids. Exemplary fatty acids are described in International Patent Publication No. WO 2020 / 014428A1, the disclosure of which is incorporated herein by reference, and include heptanoyl, 2-methylheptanoyl, 2,6-dimethylheptanoyl, 4,8-dimethylnonanoyl, 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 The fatty acid moiety has double bonds at the ω3 and ω6 positions. 18:3 , C 20:5 or C 22:6 The fatty acid portion. The fatty acid can be an ω3 or ω6 (e.g., n-3) fatty acid, an α-linolenic acid (e.g., C 18:3 ), docosahexaenoic acid (e.g., C 22:6 ) and eicosapentaenoyl (e.g., C 20:5 ) fatty acids. The fatty acids can be odd-numbered, such as heptanoyl or nonanoyl, or even-numbered, such as linolenoyl, docosahexaenoyl, or eicosapentaenoyl. These long-chain unsaturated fatty acids can be used for specific fatty acid oxidation disorders, such as medium-chain acyl-CoA dehydrogenase deficiency (MCADD). The fatty acids can be medium-chain (e.g., C 6-12 , but not for MCADD) or short chains (e.g., C 1-5 )fatty acid.

[0110] Serine (Ser) includes two reactive groups, in addition to the carboxyl group, that can be used to connect serine to a larger molecule, namely an amine group (a in the following structure) or a carboxyl group (b in the following structure) at the Cα position. Ser can be conjugated (covalently linked) to the carboxyl group of the adipic acid portion or the methylmalonic acid portion through its amine to form an amide bond ("a" in the following structure), or to form an ester bond ("b" in the following structure) through the hydroxyl group of its R group, and in this case, the O-linked (ester-linked) D-Ser is referred to herein as -OD-Ser. Please note that in the following text, the terminal amino acid is D-Ser, but one or more additional amino acids can be optionally linked to Ser through the carboxyl group to form an amide (peptide) bond. The dashed bond line refers to the bond connecting the depicted portion to the rest of the molecule (not shown). Chirality is not depicted.

[0111]

[0112] The compound may have the following structure:

[0113]

[0114] For example, adipic acid-R3 (as shown, the adipic acid moiety is linked to R3), wherein R1 and R2 are independently H, OH (hydroxyl) or O (e.g., forming a carbonyl or ketone moiety wherein O is linked by a double bond), wherein at least one of R1 and R2 is H, and R3 is linked to the adipic acid moiety by an ester bond (—O-linked) or an amide bond (—N-linked), and may include any combination of one to three amino acids selected from the group consisting of D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Asp, D-Asn, D-Leu or D-Val. For example, and without limitation, contemplating inclusion of one or more of D-Ser, D-Ala, and D-His, R3 can be: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-OD-Ser, -D-His-D-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -OD-Ser-D-Ala-D-Ser-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-His-OD-Ser, -D-Ser-D-His, -D-Ala-OD-Ser or -D-Ala-D-His. Similarly, for R3, all permutations of 1-3 amino acids selected from the group consisting of D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu and D-Val are contemplated. Furthermore, in each arrangement, the adipic acid group may be replaced by another dicarboxylic acid or a straight or branched chain fatty acid selected from a different adipic acid, methylmalonic acid, succinic acid, glutaric acid, alpha-ketoglutaric acid, an even chain fatty acid or a branched chain fatty acid.

[0115] For example, in the case where the serine residue is D-Ser, which is linked to the adipic acid moiety residue via its R group (-CH2OH, referred to herein as -OD-Ser-), the compound has, for example, the following structure:

[0116] For example,

[0117] For example, adipate-O-Ser-R4 (left) or adipate-OD-Ser-R4 (right), wherein R4 is or includes: -OH, -His-Ala, -Ala-His, -Ala or -His, wherein one, two or all of the Ser, Ala or His amino acid residues present are in the D configuration, for example, R4 is or includes: -OH, -D-His-D-Ala, -D-Ala-D-His, -D-Ala or -D-His.

[0118] The compound may have the following structure:

[0119] For example, methylmalonic acid-R5, wherein R5 is linked to the methylmalonic acid moiety via an ester bond (-O-linked) or an amide bond (-N-linked), and may include any combination of one to three amino acids selected from the group consisting of D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Asp, D-Asn, D-Leu, or D-Val. For example, and without limitation, contemplating inclusion of one or more of D-Ser, D-Ala, D-Lys, D-Leu, and D-His, R3 can be: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-His-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D-Ser- D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-Ser-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Se r, -D-His-D-Ala, -D-His-D-Ser, -D-His-OD-Ser, -D-Ser-D-His, -D-Ala-OD-Ser, -D-Ala-D-His, D-Leu-D-His, or -D-Lys-D-His. Likewise, for R5, all permutations of 1-3 amino acids selected from the group consisting of D-Ser, -OD-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, and D-Leu are contemplated.

[0120] For example, in the case where the serine residue is D-Ser, which is linked to the methylmalonic acid residue via its R group (-CH2OH, referred to herein as -OD-Ser-), the compound has, for example, the following structure:

[0121] For example,

[0122] For example, methylmalonic acid-O-Ser-R6 (left), or methylmalonic acid-OD-Ser-R6 (right), wherein R6 is or includes: -OH, -His-Ala, -Ala-His, -Ala or -His, wherein one, two or all of the Ser, Ala or His amino acid residues present are in the D configuration, for example, R6 is or includes: -OH, -D-His-D-Ala, -D-Ala-D-His, -D-Ala or -D-His.

[0123] Non-limiting examples of such compounds include: PMA001, for example, 4-hydroxyadipate-OD-Ser; PMA002, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA003, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA004, for example, 2-oxoglutarate-D-2-hydroxyglycine-D-Ala; PMA005, for example, 2-oxoglutarate-OD-Ser-D-Ala; PMA006, for example, 4 -ketoadipate-OD-Ser; PMA007.1, for example, 4-ketoadipate-OD-Ser-D-His; PMA008, for example, 2-ketoglutarate-OD-Ser-D-His; PMA009, for example, 2-ketoglutarate-D-Ala-D-His; PMA010.1, for example, 4-ketoadipate-D-Ala-D-His; PMA007, for example, methylmalonate-OD-Ser-D-His; PMA011, for example, methylmalonate PMA014, for example, adipic acid-D-Ser-D-His, and PMA015, PMA016, PMA017, PMA018, PMA019 or PMA020, which includes adipic acid, glutaryl, succinyl, heptanoyl, 2,6-dimethyl The R groups of heptanoyl, 4,8-dimethylnonanoyl and 6-amino-2,4-dimethylheptanoyl are attached to: RD-lysyl-D-glutamyl-D-histidine (PMA015), RD-lysyl-D-glutamine (PMA016), RD-lysyl-D-aspartyl-D-histidine (PMA017) or RD-lysyl-D-asparagine (PMA018), RD-leucyl-D-histidine (PMA019) and RD-lysyl-D-histidine (PMA020). Figures 1A-1C , 5 and 6 depict these exemplary structures.

[0124] Fig.17A and 17B Additional examples of useful moieties for A and B are provided, and conditions under which specific moieties are expected to be useful for treating various indications, and contraindications are included. In further detail, Fig.17A and 17B The functional contributions of this class of compounds as potential parts of anaplerosis are described, as well as the modes of action and catabolic pathways. Potential D-amino acids can be used in combination with specific fatty acids. For PA and MMA, propionic amino acids and propionic fatty acids (including branched and odd-chain amino acids and fatty acids) are contraindicated.

[0125] In the treatment of propionic acidemia or methylmalonic aciduria, the method may also include co-administering an inhibitor to the patient together with the above-mentioned compound, the inhibitor blocks the formation of propionyl-CoA acid or methylmalonic aciduria in propionic acidemia or methylmalonic aciduria, respectively. Co-administration refers to the administration of a second active agent with a first active agent (e.g., as described above) during the course of treatment. The second active agent may be administered before, after, or simultaneously with the first active agent, and may be formulated into the same unit dosage form. In one example, the inhibitor that blocks the formation of propionyl-CoA acid or methylmalonic aciduria is 2,2-dimethylbutyric acid, sodium 2,2-dimethylbutyrate, or a 2,2-dimethylbutyrate preparation, or any inhibitor that limits the function of propionyl-CoA carboxylase.

[0126] In addition, as described herein, propionyl-CoA / methylmalonyl-CoA (P-CoA / MM-CoA) formation inhibitors can be administered to patients as adjuvant therapy together with compounds described herein. For example, P-CoA / MM-CoA formation inhibitors can be HST5040 (e.g., see 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).

[0127] Propionic acidemia: Propionic acidemia is an autosomal recessive metabolic disorder. It is caused by a deficiency in 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 valine, isoleucine, methionine, and threonine catabolism and odd-chain fatty acid beta-oxidation, and is also a byproduct of branched-chain fatty acid beta-oxidation including phytanic acid and pristanic acid. PCC deficiency leads to the accumulation of propionyl-CoA, which sulfhydrylates to release toxic amounts of propionate, and is accompanied by a deficiency of its downstream pathway end product, succinyl-CoA, an intermediate of the TCA cycle, and severely leads to circulatory dysfunction. Not surprisingly, some fatty acid beta-oxidation disorders and propionic acidemia present as a common phenotype with cardiomyopathy.

[0128] PA Clinical features: The 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, with high mortality in early onset. Severe hyperammonemia results in acute neonatal encephalopathy. Hyperammonemia is attributed to inhibition of N-acetylglutamate synthesis caused by excess propionyl-CoA, an activator of carbamoyl-phosphate synthetase. Mortality is high in early onset of the disease. Also common is a more chronic course that presents with episodes of poor feeding and vomiting, ketoacidosis caused by infection, growth retardation, and osteoporosis severe enough to cause pathological fractures within the first few months of life. Developmental delay due to hyperammonemia or chronic illness is common. Metabolic stroke due to acute degeneration of the basal ganglia may occur during or between episodes of ketoacidosis. Cardiomyopathy, which can be rapidly fatal, often occurs and is unresponsive to carnitine. Pancreatitis is a recognized complication of this disease as well as chronic kidney disease.

[0129] Treatment is directed toward shock, acidosis, hypoglycemia, and hyperammonemia with fluids, bicarbonate, glucose, and dialysis. Restriction of dietary natural protein (or propionic amino acids) to the amount necessary to support normal growth and development is indicated, and typically results in natural protein intake of less than 1 g / kg / day. Liver transplantation is commonly employed and reduces the risk of episodes of metabolic decompensation and can reverse cardiomyopathy.

[0130] Anaplerotic Therapy: Over two decades ago, proof-of-concept that anaplerotic compounds using L-malate as an intermediate of the Krebs cycle could be therapeutic was reported. The study was performed in vitro using a rat liver mitochondrial assay. The researchers reported that L-malate treatment reduced propionyl-CoA levels in the mitochondrial matrix by 62% and reduced propionate levels by 46%. In a clinical study initiated in 2008, anaplerotic compounds such as glutamine, citrate, and ornithine alpha-ketoglutarate were tested on PA patients, and the authors concluded that citrate supplementation could be beneficial in some cases because it helps replenish depleted Krebs cycle intermediates. Despite the positive results in these studies, the way these anaplerotic compounds are delivered to their target sites in the mitochondria may be a major obstacle for these compounds to bring about effective therapeutic outcomes.

[0131] Methylmalonic aciduria (MMA). Methylmalonic aciduria can be caused by a genetic deficiency of methylmalonyl-CoA mutase, which is a downstream enzyme of PCC and an enzyme that requires adenosylcobalamin. It converts L-methylmalonyl-CoA to succinyl-CoA, or is in the metabolic pathway that catalyzes the biosynthesis of adenosylcobalamin from vitamin B12. When the latter defect occurs in the proximal step (which also impairs the synthesis of methylcobalamin), homocysteine ​​accumulates after the blockade of N5-methyltetrahydrofolate:homocysteine ​​methyltransferase.

[0132] MMA Clinical Manifestations: Clinical manifestations of complete methylmalonyl-CoA mutase deficiency include the usual symptoms of propionic acidemia. Severe ketoacidosis, hyperammonemia, and thrombocytopenia are common in the first few days or weeks of life. Patients with some residual mutase activity later present with a variety of symptoms, including intermittent ataxia, recurrent vomiting, growth retardation, and developmental delay. Life-threatening episodes of decompensation, whether severe or mild, can occur, usually due to minor intercurrent illnesses.

[0133] Patients with cblA and cblB defects usually suffer from single methylmalonic aciduria, but the condition is slightly milder. The mutation of the SUCLA gene is a new cause of methylmalonic aciduria, and the SUCLA gene encodes the ATP-forming subunit of the Krebs cycle enzyme succinyl-CoA ligase. The ill patient has a serious phenotype, including hypotonia, muscle atrophy, hyperkinesia, mental retardation, growth stagnation, atrophy of brain centers and cortex, and atrophy of the basal ganglia. The mutation of the CblC gene causes combined methylmalonic aciduria and homocystinemia. CblC deficiency is most common in infancy and has serious clinical manifestations, including basal ganglia necrosis, microcephaly, growth retardation, intellectual disability, retinopathy, and megaloblastic anemia. The CblD mutation can cause a combined disease as seen in CblC deficiency patients, but variants with single methylmalonic aciduria and single homocystinemia have been determined. Patients with deficiencies in the CblE and CblG groups are deficient only in methylcobalamin biosynthesis and have homocystinuria without methylmalonic aciduria. CblF deficiency results in a defect in the transport of B12 out of the lysosomes and combined methylmalonic aciduria and homocystinemia. As with propionic acidemia, treatment of acute episodes of metabolic decompensation is first directed toward treating shock, acidosis, hypoglycemia, and hyperammonemia, followed by protein restriction (particularly propionic acidogenic amino acids). Carnitine is used to treat secondary carnitine deficiency. Some patients treated in this manner do well, but many do poorly and die in early childhood, usually during an episode of ketoacidosis. Liver transplantation or liver / kidney transplantation can reduce severity but cannot cure the disease.

[0134] Defects in long-chain fatty acid oxidation lead to a marked reduction in lysine succinylation of mitochondrial proteins and are part of the pathological mechanism. Collectively as a group, defects in MCAD, VLCAD, LCHAD, TFP, and CPT II are the most common metabolic defects identified by newborn screening using tandem mass spectrometry.

[0135] It is necessary to treat patients with mitochondrial fatty acid β oxidation deficiency, such as therapies for the treatment of patients with MCAD, VLCADD, LCHADD, TFPD or CPT IID deficiency, to minimize the less life-threatening decompensation episodes that occur in most patients who need frequent hospitalization within the first 2-3 years after birth. In young patients, adults and elderly patients, a healthy exercise tolerance lifestyle is also important for avoiding other common late-onset diseases. U.S. Patent No. 8,399,515 describes C5 and C15 fatty acids that can be used to treat fatty acid disorders, and WO / 2000045649 describes C7 fatty acids for the treatment of fatty acid disorders, for example, n-heptanoic acid, which leads to the development of triheptanoin. It is desirable to use additional and / or more optimal compositions for the treatment of fatty acid disorders. It has also been reported that medium branched-chain fatty acids are used as an alternative treatment to compensate for the exhaustion of succinyl-CoA (US WO2020014428 A1). Example

[0136] There are three major pathways to maintain succinyl-CoA at its physiological optimum level. These pathways are the TCA cycle, amino acid catabolism, and branched and odd-chain fatty acid β-oxidation. The normal function of these three pathways is crucial. The deficiency of the enzymes that catalyze any of the three pathways will lead to disease. Propionic amino acids (valine, isoleucine, methionine, and threonine) catabolism and branched and odd-chain fatty acid β-oxidation generate propionyl-CoA. In the absence of a normal supply of propionyl-CoA from any of these pathways, or in the case of PA and MMA, the supply of succinyl-CoA is severely affected, and succinyl-CoA can be supplemented by the TCA cycle, provided that the administered compound metabolic pathway will undergo decomposition and cannot be directly used as a building block for the biosynthesis of active larger molecules. The building blocks of the proposed compounds include D-histidine plus D-alanine or D-serine, where the former will directly supply α-ketoglutarate (a precursor of succinyl-CoA in the TCA cycle), and D-alanine will undergo deamination to pyruvate, which can be broken down by pyruvate dehydrogenase for full utilization in the TCA cycle, or can still be used in gluconeogenesis. D-serine will be deaminated and can be reaminated back to L-serine or broken down to glycine, which can be used for conjugation with propionate, or can enter other pathways. It is assumed that adipic acid or its derivatives (see below) leads to the provision of one acetyl-CoA and one succinyl-CoA.

[0137] Compound:

[0138] Three compounds related to the present disclosure, dicarboxylic acid acyl-D-dipeptides, were designed as follows: (1) top structure, Figure 5, adipic acid-DO-Ser-D-His (PMA007), wherein the connection between adipic acid and D-Ser is through an ester bond, and D-Ser and D-His are connected through a peptide bond. (2) Bottom structure, Figure 5 , adipate-D-Ala-D-His (PMA010), in which the three parts are connected by peptide bonds. (3) Top structure, Figure 6 , methylmalonic acid-D-Ala-D-His (PMA011), in which the three parts are connected by peptide bonds. In addition, for two compounds PMA019 (intermediate structure, Figure 6 , methylmalonic acid-D-Leu-D-His) and PMA020 (bottom structure, Figure 6 , methylmalonic acid-D-Lys-D-His) was tested on a limited basis and data were obtained.

[0139] Materials and methods

[0140] Compound synthesis: dicarboxylic acid acyl-D-dipeptide; PMA007, PMA010, PMA011, PMA019 and PMA020 were synthesized by solid phase synthesis on a Liberty microwave synthesizer (CEM Corporation, 3100 Smith Farm Road, Mathews, NC 28106) using the FMOC synthesis scheme. (Peptide & Peptoid Synthesis Facility, University of Pittsburgh Health Sciences Core Research Facilities). In short, the synthesis was carried out by adding activated amino acid residues to a solid support (Wang resin) starting from the carboxyl terminal to the amino terminal. The activation of amino acids was carried out by DIC-Oxyma chemistry. At the end of the synthesis, PyBop / DIPEA chemistry was used to conjugate the peptide PMA010 with adipic acid and methylmalonic acid, respectively, overnight, and the coupling efficiency was confirmed by the ninhydrin test. In addition, PyBop / DMAP coupling conditions were used to couple adipic acid to the Ser-hydroxyl group of compound PMA007. Finally, the peptide was cleaved from the resin by 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 reversed-phase high performance liquid chromatography (RP-HPLC, 486 and 600E of Waters Corporation), and subsequently confirmed to have the correct mass on a Bruker Ultraflextreme MALDI Tof / Tof mass spectrometer.

[0141] Cell lines and culture: All proof-of-concept testing was performed in vitro on fibroblasts from patients (multiple) with propionic acidemia and methylmalonic acidemia to test both compounds.

[0142] Table 1. Names, genotypes, and phenotypic data of fibroblast cell lines used in this study.

[0143]

[0144] A control fibroblast cell line FB826 was used to estimate the amount of succinyllysine detectable in "normal" cells using an anti-succinyllysine antibody.

[0145] Immunohistochemistry: Patient cells were counted at 3-5 x 10 4 The cells were grown in glass coverslips at a seeding density of 100 cells / mL. The culture medium for the untreated and treated groups did not have glucose, glutamine or pyruvate, and contained lipid-stripped FBS instead of regular FBS. The fluorescence intensity from 50-60 cells in each group was quantified using NIH Image J software. Immunocytochemical staining of anti-succinyl lysine (green), anti-MTCO1 (red) or anti-TOMM20 antibodies was performed on the fibroblast cell line of a patient with propionic acidemia (Fb859), and DAPI (blue) staining was performed for the nuclei. Instrument: Zeiss LSM 710 confocal microscope. Statistical analysis used Tukey's multiple range test. ****P<0.0001, the [PMA010] (90 μM) treatment group was statistically compared with control cells grown in the presence of regular complete DMEM medium, untreated and [PMA010] (30 μM) cells grown in the absence of glucose / pyruvate / L-glutamine.

[0146] Measurement of mitochondrial respiration Seahorse: Fb859 cells were grown in regular DMEM medium until 85-90% confluence. Cells were harvested and seeded in regular DMEM medium at a concentration of 25,000 cells / 80 μl (n=8 replicates) in poly-D-lysine coated XFe seahorse 96-well plates and incubated overnight at 37°C in a 5% CO2 incubator. The next day, the medium was replaced with the following in the designated wells for 72 h: 180 μl of special medium A (seahorse XFDMEM basal medium + 10% fat-stripped FBS + glucose + sodium pyruvate + L-glutamine + 0.5 mM carnitine). 180 μl of special medium B (seahorse XFDMEM basal medium + 10% fat-stripped FBS + 0.5 mM carnitine, and no added glucose, sodium pyruvate or glutamine). 180 μl of special medium B containing experimental compounds. After 72h incubation, special media A and B were replaced with 180 μL Seahorse XF DMEM basal media (containing glucose, sodium pyruvate, L-glutamine or completely free of glucose, sodium pyruvate, L-glutamine) in the corresponding designated wells and incubated at 37°C for 1h in a non-CO2 incubator before measurement. OCR was determined (Seahorse XF MitoStress test). Finally, cells were lysed and protein content was determined. Data were normalized to protein concentration, and OCR was reported in pmol / min / mg protein.

[0147] Detection of ETC components by Western blotting: Same as above, in T75 flasks, medium A was used for controls and medium B was used for untreated and treated cells. When the culture was about 85-90 confluence, the amount of compound was added directly to the cell culture medium appropriately. The culture was allowed to grow for 72 h at 37°C / 5% CO2 and then harvested. The harvested cell pellets were stored at -80°C until immuno- and enzymatic assays of OXPHOS subunits and Western blot analysis were performed. 1 to 1.5 ml culture medium samples were also stored at -80°C.

[0148] Measurement of mitochondrial respiration: Control Fb826 and patient Fb859 cells were grown in regular DMEM medium without additional glutamine until 85-90% confluence. Cells were harvested and plated at a concentration of 25,000 cells / 80 μL (n=8 replicates) in regular DMEM medium without additional glutamine in poly-D-lysine-coated XfeSeahorse 96-well plates and incubated overnight at 37°C in a 5% CO2 incubator. The next day, the medium was replaced with the following in the designated wells for 72 h: (1) 180 μL of special medium A (Seahorse XFDMEM basal medium with added 10% stripped (lipid-free) FBS, glucose, sodium pyruvate, L-glutamine, and 0.5 mM carnitine). (2) 180 μL of special culture medium B (seahorse XF DMEM basal medium, 10% stripped FBS and 0.5 mM carnitine, and without glucose, sodium pyruvate or glutamine). (3) 180 μL of special culture medium B containing "reference compounds" (30, 90, 150 μM) D-serine, D-histidine or adipic acid and a combination of 90 μM D-serine + D-histidine and adipic acid, or experimental compounds 30 μM or 90 μM PMA007 or PMA010. After 72 h incubation, special culture medium A and B were replaced with 180 μL Seahorse XF DMEM basal medium (containing glucose, sodium pyruvate and L-glutamine or without these three components or experimental compounds) in the corresponding designated wells and incubated at 37°C for 1 h in a non-CO2 incubator and then measured on the XFeSeahorse instrument from Agilent. 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 to protein concentration and OCR was reported in pmol / min / mg protein.

[0149] Acylcarnitine levels were determined: Culture media from control Fb826 and treated and untreated patient Fb859 cells were collected from immunohistochemistry cultures or Seahorse oxygen consumption 96-well plate assays and analyzed using an ExionLC TM 100HPLC system (Shimadzu Scientific Instruments TM , Columbia, MD) with a triple quadrupole API4000 mass spectrometer (AB Sciex TM , Framingham, MA) were analyzed for levels of short-chain acylcarnitines plus propionylglycine and hydroxypropionylglycine as outlined previously.

[0150] Measurement of mitochondrial ROS production using MitoSOX Red as a superoxide indicator probe: Control (Fb826), PA patients (Fb859, Fb900) and GA II patients (Fb930, Fb961) fibroblasts were grown in regular DMEM medium containing glucose / pyruvate / L-glutamine until 85-90% confluence. Cells were harvested and seeded at a concentration of 25,000 cells / 80 μl (n=3) in regular DMEM medium containing glucose / pyruvate / L-glutamine in a cell culture treated black wall 96-well microplate with a clear bottom and incubated overnight at 37°C in a 5% CO2 incubator. The next day, the medium was replaced with the following in the designated wells for 72 h: 150 μl regular DMEM (glucose + 10% FBS + sodium pyruvate + L-glutamine + 0.5 mM carnitine). In control and propionic acidemia patient fibroblasts, 150 μl of regular DMEM containing the experimental compound (180 and 640 μM) PMA010 or PMA011 or PMA019 and (640 μM) PMA020. In Fb930, 150 μl of regular DMEM containing the experimental compound (600 and 1200 μM) PMA011, and in Fb961 GA II patient fibroblasts, 150 μl of regular DMEM containing (1200 μM) PMA011. After 72 h incubation, the wells were washed twice with 150 μL of Seahorse XFDMEM basal medium, and the following assay buffer (150 μL of seahorse XFDMEM basal medium containing glucose, sodium pyruvate and glutamine) and 5 μM MitoSOX reagent were used in the corresponding designated wells and incubated in a 37°C non-CO2 incubator in the dark for 15 minutes. After 15 minutes of incubation, cells were washed twice with 150 μL of seahorse XFDMEM basal medium and replaced with the same measurement buffer as the cleaning buffer. Fluorescence was monitored when excited at 520 nm and emitted at 580 nm. Finally, cells were lysed and protein content was determined. Data were normalized to protein concentration, and fluorescence was reported as MitoSOX Red (AFU) / mg protein.

[0151] Results and Discussion

[0152] Five biomarkers were evaluated to measure the effectiveness of the compounds at the cellular level in terms of lysine succinylation, specific OXPHOS subunit Western blot patterns, O2 consumption rate parameters, C3 acylcarnitine species analysis, and effects on reactive oxygen species.

[0153] Restoration of lysine succinylation: Figure 7Comparison of lysine succinylation of cellular proteins visualized by immunofluorescence confocal microscopy in untreated and treated PA patients (Fb859) with PMA010 and PMA011 or individual components of these two compounds (including adipic acid and methylmalonic acid, compared to succinic acid) is shown. Green staining was significantly increased in all treatments compared to untreated cells.

[0154] Figures 8A-8F is a comparison of 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 and containing stripped FBS. Figure 8B The restoration of the lysine succinylation (green) signal in the presence of D-serine is shown and is consistent with Fig. 8A For comparison, untreated Fb859 was used. Figure 8C Shown is the recovery of lysine succinylation (green) signal in the presence of 30 μM and 90 μM PMA007. Fig.8D The recovery of the lysine succinylation (green) signal in the presence of 30 μM and 90 μM PMA010 is shown. Yellow indicates co-localization of lysine succinylated proteins and mitochondrial MTCO1 subunits stained with anti-MTCO1 (red) antibodies. DAPI (blue) was included as a counterstain. Fig. 8E The bar graphs for D-serine and PMA007 treatment data are from Fig. 8A and 8B Quantification of images. Fig. 8E The D-serine and PMA010 treatment data in the bar graph are from images collected from duplicate D-serine treatment experiments and from Fig.8D Quantification of images collected from PMA010 treatment.

[0155] Figures 9A-9F is in human HEK293 control and untreated and treated HEK293PCCA - / - Comparison of lysine succinylation of cellular proteins in knockout cells visualized by immunofluorescence confocal microscopy. Fig. 9B , 9C and 9D, cells were grown in medium lacking glucose, pyruvate, and glutamine. Fig. 9B Figure 2 shows that in the absence of glucose, pyruvate, and glutamine, a substantial loss of lysine succinylation (green) signal was observed in both control and knockout cells. However, treatment of PCCA with 30 μM and 90 μM PMA007 - / - cell( Fig. 9C ), or treated with 30μM and 90μM PMA010 ( Fig.9D) restores green, indicating restoration of lysine succinylation. Yellow indicates colocalization of lysine succinylated proteins and mitochondrial MTCO1 subunits stained with anti-MTCO1 (red) antibody. DAPI (blue) was included as a counterstain. Fig.9E The bar graph of the PMA007 treated data is Fig. 9C Images and Fig. 9B Quantification compared with untreated controls. Fig.9F The bar graph of the PMA010 treatment data is Fig.9D Images and Fig. 9B Quantification compared with untreated controls.

[0156] ETC subunit deficiencies in PA and MMA: Fig.10 The control Fb826 controls normal levels and the reduction of signals of various ETC components in PA and MMA cells are shown. 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 ETC subunits were used together as biomarkers, and changes were observed in the case of treatment, see below.

[0157] Fig.11 Correction of the signals of complex III subunit core 2 48-kDa (UQCRC2), complex IV subunit II 22-kDa (COXII), and complex I subunit NDUFB8 18-kDa is shown, most notably in the propionic acidemia (PA) cell line Fb859 compared to the methylmalonic aciduria (MMA) cell line Fb857. PMA010 appears to have a better effect than PMA007. Complex II subunit core 2 (UQCRC2) was improved in untreated cells (no glucose, pyruvate, or fat in the culture medium).

[0158] O2 consumption parameters: Fig. 12A-12F, changes in oxygen consumption rate in PA patient cells Fb85972h treated with 30μM and 90μM of D-serine, D-histidine, adipic acid, PMA007 and PMA010 with the addition of different ETC inhibitors were compared with changes in response to 30μM and 90μM treatment of individual components for 72h. Data are reported as mean ± SD. Repeat n = 5-8. Data were tested for normal distribution by Shapiro-Wilk test. Variance was homogeneous (p>0.05) and data followed a normal distribution (p>0.05). *P<0.05, **P<0.01, ***P<0.001 (one-way analysis of variance (ANOVA), followed by post hoc Tukey multiple range test when F was significant). ns: not significant. Overall, oxygen consumption parameters were improved in the presence of the tested compounds when compared to the individual components D-serine and D-histidine in addition to adipic acid. More detailed studies are needed to identify the importance of the contribution of the D-amino acid component of the PMA family of compounds in replenishing Krebs cycle compound intermediates compared to acting as a carrier for the dicarboxylic acid component.

[0159] O2 consumption parameters: Figures 13A-13H , in response to the use of PMA010( Figures 13A-13D ) and PMA011( Fig.13E -13J) Changes in oxygen consumption rate of PA patient cells Fb859 with the addition of different inhibitors. The data in these figures are provided as percentage changes relative to untreated cells. Although basal respiration can represent oxygen consumption in the resting state and is therefore a function of cellular stress, the changes in reserve capacity are significant, up to 3-4 times that of untreated, indicating the effectiveness of these two compounds in improving the bioenergetics of the cells.

[0160] Acylcarnitine Evidence: Figures 14A-14D , in Fb859 cells and HEK293 PCCA containing PMA007 or PMA010 - / - Propionylcarnitine in the cell culture medium ( Fig.14A ), propionylglycine ( Fig. 14B ), Hydroxypropionylcarnitine ( Fig. 14C ) and hydroxypropionylglycine ( Fig.14D ) quantification. The reduction detected in the alternative metabolites of propionyl-CoA is significant as a primary biomarker of disease. Excess propionyl-CoA is thiolyzed to acid and converted primarily in the liver to four metabolites, of which carnitine and glycine are detoxifiers. PMA010 appears to be effective in HEK293 PCCA - / -The cells were more efficient, resulting in a decrease in propionylcarnitine (59% decrease), propionylglycine (41% decrease), and hydroxypropionylglycine (80% decrease). Media samples were processed for mass spectrometry as indicated in Materials and Procedures below.

[0161] Evidence for the effect of PMA compounds on reducing detectable reactive oxygen species (ROS) in PA and GA II cells: Figures 15A-15D Shown are the levels of ROS, a biomarker associated with the development of cellular stress in untreated PA cells, and the effects of treatment with different amounts of PMA010, PMA011, PMA019, and PMA020 on control FB826 ( Fig.15A )、FB859 PA cells( Fig. 15B ) and FB900 PA cells ( Fig. 15C ) in the control cells (FB826) ( Fig.15A ) and another PA cell line FB900 ( Fig. 15C ) and PMA011 was equally effective in FB900 ( Fig. 15C Preliminary testing of the effects of PMA011 on GA II (glutaric acidemia II) FB930 and FB961 cell lines also showed a significant reduction in ROS after treatment compared to no treatment ( Fig.15D ).

[0162] Evidence for reduced lysine succinylation in disorders of fatty acid β-oxidation: Fig.16 A significant reduction in the antigenic signal for succinyllysine (green staining) in fatty acid oxidation disorders as indicated - severe lysine hyposuccinylation. Of note, in the case of control normal cell lines, the yellow color indicates the overlap of the signals for succinyllysine (green) and anti-MTCO1 (mitochondrial marker, red). In TFP, CPTII and VLCAD cell lines, red predominates, indicating reduced lysine succinylation.

[0163] Conclusion: The results are all consistent and unequivocal, indicating the effectiveness of all three compounds at a molecular level in PA cells (propionyl-CoA carboxylase deficient) in terms of being a rich source of succinyl-CoA, although PMA010 showed slightly better performance in the in vitro model. Although media propionyl-carnitine appears to drop slightly by 15%, propionyl-carnitine is artificially high to begin with, as cells are deprived of glucose, pyruvate, or fatty acids under the experimental conditions used, forced to use amino acids for energy. In MMA, the performance of the compounds was not as dramatic, and is presumably due to methylmalonyl-CoA competing to modify the same reactive lysine sites targeted by succinyl-CoA. This suggests that PCC inhibitors may work synergistically with PMA010 to compensate for the lack of succinyl-CoA, while PCC inhibitors limit the accumulation of methylmalonyl-CoA.

[0164] The present invention has been described with reference to certain exemplary embodiments, dispersible compositions and uses thereof. However, one of ordinary skill in the art will recognize that various substitutions, modifications or combinations may be made to any of the exemplary embodiments without departing from the spirit and scope of the present invention. Therefore, the present invention is not limited by the description of the exemplary embodiments, but rather by the appended claims as originally filed.

Claims

1. A method of providing a repletion compound to a patient in need thereof, comprising administering to the patient a compound having structure AB or BA', wherein: A comprises a dicarboxylic acid, a tricarboxylic acid or a straight-chain or branched-chain fatty acid moiety selected from the group consisting of adipic acid, 3-hydroxyadipic 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, a straight-chain fatty acid or a branched-chain fatty acid; A' comprises a straight or branched fatty acid moiety selected from: 6-hydroxyhexanoic acid (the hydroxyl group is linked to the B carboxylic acid as an ester bond), 6-aminohexanoic acid (linked to the B carboxylic acid through an amide bond) or 6-amino-2,4-dimethylheptanoic acid (linked to the B carboxylic acid through an amide bond); and B is an amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from the following: 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 through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or is linked to A' through an ester bond or an amide bond, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the compound has structure AB, wherein: A comprises an adipic acid moiety or a methylmalonic acid moiety; and B comprises 1-3 D-amino acids selected from D-Ser, D-Ala, D-Lys, D-Leu or D-His, which are linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof, for use in treating fatty acid oxidation disorders.

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

4. A method of treating a patient suffering from propionic acidemia (PA), methylmalonic aciduria (MMA) or a fatty acid oxidation disorder and having abnormally low amounts of anaplerotic intermediates, comprising administering to the patient a compound having structure AB or BA', wherein: a. For the treatment of PA, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, methylmalonic acid, citric acid, isocitric acid, oxaloacetic acid, α-ketoglutaric acid, A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from the group consisting of 6-hydroxyhexanoic acid, 6-aminohexanoic acid, and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from the group consisting of D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn or D-Leu, which is linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or linked to A' via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof; b. For the treatment of MMA, A comprises a dicarboxylic acid, a tricarboxylic acid or an even-numbered straight-chain fatty acid moiety selected from the group consisting of adipic acid, glutaric acid, succinic acid, citric acid, isocitric acid, oxaloacetic acid and α-ketoglutaric acid; and A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from the group consisting of 6-hydroxyhexanoic acid or 6-aminohexanoic acid; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, comprising at least one amino acid selected from the group consisting of D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn or D-Leu, linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or linked to A' via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof; or c. For treating fatty acid oxidation disorders, A comprises a dicarboxylic acid, a tricarboxylic acid, or an even-numbered straight-chain or branched-chain fatty acid moiety selected from the group consisting of 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, an even-numbered straight-chain fatty acid, or a branched-chain fatty acid; and A' comprises an even-numbered straight-chain dicarboxylic acid or fatty acid moiety selected from the group consisting of 6-hydroxyhexanoic acid, 6-aminohexanoic acid, or 6-amino-2,4 -dimethylheptanoic acid; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of a D-amino acid, including at least one amino acid selected from the group consisting of 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 via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or is linked to A' via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the compound has structure AB, wherein: A comprises an adipic acid moiety or a methylmalonic acid moiety; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of D-amino acids, including at least one amino acid selected from D-Ser, D-Ala, D-Lys, D-Leu and D-His, which is linked to A through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof, in an amount effective to normalize the level of anaplerotic intermediates.

6. The method of any one of claims 1-5, wherein the patient has propionic acidemia (PA); transient methylmalonic aciduria (MMA) due to a defect in the cobalamin transporter receptor; methylmalonic aciduria, cblA type; methylmalonic aciduria, cblB type; 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 acidemia I (GA I or GA1); or glutaric acidemia II (GA I or GA2).

7. The method of any one of claims 1-5, wherein the compound comprises a moiety type listed in Figures 17A and 17B, and the compound is used to treat the corresponding recommended indications in Figures 17A and 17B, and, where relevant, is optionally contraindicated for treating the corresponding diseases as indicated in Figures 17A and 17B.

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

9. The method of any one of claims 1-5, wherein the patient suffers from glutaric acidemia I (GA I or GA1), while glutaric acid or lysine is not included in the compound structure, or suffers from glutaric acidemia II (GA II or GA 2), while glutaric acid or lysine, fatty acids and branched-chain amino acids are not included in the compound structure, and the fatty acids and branched-chain amino acids require ETF or ETF dehydrogenase for their breakdown.

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

11. The method of any one of claims 1-10, 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, wherein D-Ser is linked via an amide bond (-N-linked) or an ester bond (-O-linked).

12. The method of any one of claims 1-9, wherein the compound has the following structure: wherein R1 and R2 are independently H, hydroxyl, or oxygen linked by a double bond to form a ketone moiety, wherein at least one of R1 and R2 is H, and R3 is linked by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of 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 the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-OD-Ser, -D-His-D-Ser-D-Ala, -D-H is-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-Se r-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-OD-Ser, -D-Ser-D-His, -D-Ala-OD-Ser, or -D-Ala-D-His.

13. The method of any one of claims 1-9, wherein the compound has the following structure: wherein R5 is linked by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of 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 the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-OD-Ser, -D-His-D-Ser-D-Ala, -D-His-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, - -D-Ala la-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-OD-Ser, -D-Ser-D-His, -D-Ala-OD-Ser, -D-Ala-D-His, -D-Leu-D-His, or -D-Lys-D-His.

14. The method of any one of claims 1-9, wherein the compound is selected from the group consisting of: PMA001, for example, 4-hydroxyadipate-OD-Ser; PMA002, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA003, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA004, for example, 2-ketoglutarate-D-2-hydroxyglycine-D-Ala; PMA005, for example, 2-ketoglutarate-OD-Ser-D-Ala; PMA006, for example, 4-ketoadipate-OL-Ser; PMA007.1, for example, 4-ketoadipate-OD-Ser-D-His-succinyl-CoA; PMA008, for example, , 2-ketoglutarate-OD-Ser-D-His; PMA009, for example, 2-ketoglutarate-D-Ala-D-His; PMA010.1, for example, 4-ketoadipate-D-Ala-D-His; PMA011, for example, methylmalonate-OD-Ser-D-His; PMA012, for example, methylmalonate-D-Ala-D-His; PMA013, for example, adipate-D-Ala-D-Ser-D-His; PMA014, for example, adipate-D-Ser-D-His; PMA019, for example, methylmalonate-D-Leu-D-His; and PMA020, for example, methylmalonate-D-Lys-D-His.

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

16. The method of any one of claims 1-9, wherein the compound is PMA007 (Adipate-OD-Ser-D-His).

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

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

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

20. The method of any one of claims 1-11, wherein the patient has propionic acidemia, and wherein A is methylmalonic acid, excluding propionic acid-producing amino acids or fatty acids.

21. The method of claim 20, wherein the patient does not have methylmalonic aciduria.

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

23. The method of 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 of any one of claims 1-21, further comprising administering to the patient, e.g., co-administering to the patient as an adjunct therapy, an inhibitor that limits the production of propionyl-CoA or methylmalonyl-CoA from various sources.

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

26. A compound having the structure AB or B-A', wherein A comprises a dicarboxylic acid, a tricarboxylic acid, or a linear or branched fatty acid moiety selected from the group consisting of adipic acid, 3-hydroxyadipic 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, a linear fatty acid, or a branched fatty acid; A' comprises a straight or branched fatty acid moiety selected from: 6-hydroxyhexanoic acid (the hydroxyl group is linked to the B carboxylic acid as an ester bond), 6-aminohexanoic acid (linked to the B carboxylic acid through an amide bond) or 6-amino-2,4-dimethylheptanoic acid (linked to the B carboxylic acid through an amide bond); and B is an amino acid, a D-dipeptide or a D-tripeptide of an amino acid, comprising at least one amino acid selected from the group consisting of 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, linked to A through an amide bond or, in the case of D-Ser, through an amide bond or an ester bond, or linked to A' through an ester bond or an amide bond, or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26, wherein the compound has structure AB, wherein: A comprises an adipic acid moiety or a methylmalonic acid moiety; and B is a D-amino acid, a D-dipeptide or a D-tripeptide of D-amino acids, including at least one amino acid selected from D-Ser, D-Ala, D-Lys, D-Leu and D-His, which is linked to A via an amide bond or, in the case of D-Ser, via an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof.

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

29. The compound of claim 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-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 via an amide bond (-N-linked) or an ester bond (-O-linked).

30. The compound of claim 26 having the following structure: wherein R1 and R2 are independently H, hydroxyl or oxygen connected by a double bond to form a ketone moiety, wherein at least one of R1 and R2 is H, and R3 is connected by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of 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 the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ala-OD-Ser, -D-His-D-Ser-D-Ala, -D-H is-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D-Ser-D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-Se r-D-His, -D-Ala-D-His-D-Ser, -D-Ala-D-His-D-Ser, -D-His-D-Ala, -D-His-D-Ser, -D-His-OD-Ser, -D-Ser-D-His, -D-Ala-OD-Ser, or -D-Ala-D-His.

31. The compound of claim 26 having the following structure: wherein R5 is linked by an ester bond (—O-linked) or an amide bond (—N-linked), and comprises 1-3 D amino acids selected from the group consisting of D-Ser, -OD-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, and D-Val, or is one of the following: -D-Ser, -OD-Ser, -D-Ala, -D-His, -D-His-D-Ala-D-Ser, -D-His-D-Ser-D-Ala, -D-His-OD-Ser-D-Ala, -D-Ser-D-His-D-Ala, -OD-Ser-D-His-D-Ala, -D- Ser-D-Ala-D-His, -OD-Ser-D-Ala-D-His, -D-Ala-D-Ser-D-His, -D-Ala-OD-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-OD-Ser, -D-Ser-D-His, -OD-Ser-D-His-D-Ser-D-Ala, -OD-Ser-D-Ala-D-Ala-D-Ser, -D-Ala-OD-Ser, -D-Ala-D-His, -D-Leu-D-His, or -D-Lys-D-His.

32. The compound of claim 26, which is selected from: PMA001, for example, 4-hydroxyadipate-OD-Ser; PMA002, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA003, for example, 4-hydroxyadipate-OD-Ser-D-Ala; PMA004, for example, 2-ketoglutarate-D-2-hydroxyglycine-D-Ala; PMA005, for example, 2-ketoglutarate-OD-Ser-D-Ala; PMA006, for example, 4-ketoadipate-OL-Ser; PMA007.1, for example, 4-ketoadipate-OD-Ser-D-His-succinyl-CoA; PMA008, for example, 2-ketoglutarate-D-2-hydroxyglycine-D-Ala. Acid-OD-Ser-D-His; PMA009, for example, 2-ketoglutarate-D-Ala-D-His; PMA010.1, for example, 4-ketoadipate-D-Ala-D-His; PMA011, for example, methylmalonic acid-OD-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.

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