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US 2026/0021186 A1Published application
Fatty Acid-D-Amino Acid Peptides Conjugates as Anaplerotic Compounds for Use in Treating Propionic Acidemia, Methylmalonic Acidurias, and Energy Metabolic Disorders
AssigneeUniversity of Pittsburgh—Of the Commonwealth System of Higher Education
InventorAl-Walid A. Mohsen
Life of this patent
Estimating the term…
Abstract
Provided herein is a method of providing an anaplerotic compound to a patient in need therefor. The method may be used to treat the patient for a propionic acidemia. a methymalonic aciduria, or a fatty acid oxidation disorder. Also provided herein are compounds useful in those methods. the compounds comprising an adipic acid or methylmalonic acid moiety linked to from one to three amino acids, e.g. D-amino acids, such as D-Ser, D-His, D-Lys, D-Leu, and/or D-Ala.
Claims25
A method of providing an anaplerotic compound to a patient in need therefor, comprising administering to the patient a compound having the structure A-B or B-A′, where:
- A comprises a dicarboxylate, a tricarboxylic, or a straight or branched-chain fatty acid moiety selected from:
- an adipic acid, a 3-hydroxy-adipic acid, a 3-ketoadipic acid, a glutaric acid, a succinic acid, methylmalonic acid, a citric acid, an isocitric acid, α-ketoglutaric acid, an oxaloacetic acid, a heptanoic acid, a 2,6-dimethylheptanoic acid, a 4,8-dimethylnonanoic acid, a 6-amino-2,4-dimethylheptanoic acid, a straight chain fatty acid, or a branched-chain fatty acid;
- A′ comprises a straight or branched-chain fatty acid moiety selected from:
- 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid, or 6-amino-2,4-dimethylheptanoic acid and
- B is an amino acid, D-dipeptide, or D-tripeptide of D-amino acids, comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val linked to A by an amide bond or by an amide bond or ester bond in the case of D-Ser, or to A′ by an ester bond or an amide bond,
- or a pharmaceutically acceptable salt thereof.
3 more elements
A method of treating a patient having a propionic acidemia (PA), a methymalonic aciduria (MMA), or a fatty acid oxidation disorder, and having abnormally low amounts of anaplerotic intermediates, comprising administering to the patient a compound having the structure A-B or B-A′, wherein:
- a. for treating PA, A comprises a dicarboxylate, a tricarboxylic, or an even straight-chain fatty acid moiety selected from:
- an adipic acid, a glutaric acid, a succinic acid, methylmalonic acid, a citric acid, an isocitric acid, an oxaloacetic acid, α-ketoglutaric acid, A′ comprises a straight even-chain dicarboxylic or fatty acid moiety selected from:
- a 6-hydroxy-hexanoic acid, a 6-amino-hexanoic acid, and B is a D-amino acid, D-dipeptide, or D-tripeptide of D-amino acids comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu linked to A by an amide bond or by an amide bond or ester bond in the case of D-Ser or to A′ by an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof;
- b. for treating MMA, A comprises a dicarboxylate, a tricarboxylic, or an even straight-chain fatty acid moiety selected from:
- an adipic acid, a glutaric acid, a succinic acid, a citric acid, an isocitric acid, an oxaloacetic acid, and α-ketoglutaric acid;
- and A′ comprises a straight even-chain dicarboxylic or fatty acid moiety selected from:
- a 6-hydroxy-hexanoic acid or a 6-amino-hexanoic acid;
- and B is a D-amino acid, D-dipeptide, or D-tripeptide of D-amino acids, comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, or D-Leu linked to A by an amide bond or by an amide bond or ester bond in the case of D-Ser or to A′by an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof;
- or
- c. for treating a fatty acid oxidation disorder, A comprises a dicarboxylate, a tricarboxylic, or an even straight-chain or branched-chain fatty acid moiety selected from:
- an adipic acid, a glutaric acid, a succinic acid, methylmalonic acid, a citric acid, an isocitric acid, an oxaloacetic acid, α-ketoglutaric acid, a heptanoic acid, a 2,6-dimethylheptanoic acid, a 4,8-dimethylnonanoic acid, a 6-amino-2,4-dimethylheptanoic acid, an even straight chain fatty acid, or a branched-chain fatty acid;
- A′ comprises a straight even-chain dicarboxylic or fatty acid moiety selected from:
- 6-hydroxy-hexanoic acid, 6-amino-hexanoic acid, or 6-amino-2,4-dimethylheptanoic acid;
- and B is a D-amino acid, D-dipeptide, or D-tripeptide of D-amino acids, comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Thr, D-Ile, D-Val, D-Asp, D-Asn, or D-Leu linked to A by an amide bond or by an amide bond or ester bond in the case of D-Ser or to A′ by an amide bond or an ester bond, or a pharmaceutically acceptable salt thereof.
11 more elements
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15-21. (canceled)
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A compound having the structure A-B or B-A′, wherein:
- A comprises a dicarboxylate, a tricarboxylic, or a straight or branched-chain fatty acid moiety selected from:
- an adipic acid, a 3-hydroxy-adipic acid, a 3-ketoadipic acid, a glutaric acid, a succinic acid, methylmalonic acid, a citric acid, an isocitric acid, α-ketoglutaric acid, an oxaloacetic acid, a heptanoic acid, a 2,6-dimethylheptanoic acid, a 4,8-dimethylnonanoic acid, a 6-amino-2,4-dimethylheptanoic acid, a straight chain fatty acid, or a branched-chain fatty acid;
- A′ comprises a straight or branched-chain fatty acid moiety selected from:
- 6-hydroxy-hexanoic acid (hydroxyl linked to B carboxylate as an ester bond), 6-amino-hexanoic acid, or 6-amino-2,4-dimethylheptanoic acid;
- and
- B is an amino acid, D-dipeptide, or D-tripeptide of amino acids, comprising at least one amino acid selected from D-Ser, D-Ala, D-His, D-Lys, D-Glu, D-Gln, D-Asp, D-Asn, D-Leu, D-Ile, D-Thr, or D-Val linked to A by an amide bond or by an amide bond or ester bond in the case of D-Ser, or to A′ by an ester bond or an amide bond,
- or a pharmaceutically acceptable salt thereof.
4 more elements
28-29. (canceled)
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Dependencies are inferred from the claim text.