Methods of treating disorders associated with castor
The present disclosure relates to methods of treating a coenzyme A reduction, elevation, sequestration, toxicity, or redistribution (CASTOR) disease such as, for example, defects in fatty acid oxidation enzymes, methylmalonic acidemia, glutaric acidemia, propionic academia, and HMG-CoA lyase, via small molecule modulators of CoA levels. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A method of treating propionic acidemia (PA) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure represented by a formula:
or a pharmaceutically acceptable salt thereof,
wherein:
A is CH 2 ;
Q 1 is CH; and R 2 is selected from —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy; or
Q 1 is N; and R 2 is selected from halogen, —SCH 3 , C1-C8 acyclic alkyl, C2-C8 acyclic alkenyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxyhaloalkyl, cyclopropyl, cyclobutyl, and oxetane, wherein the cyclopropyl, cyclobutyl, and oxetane are optionally substituted with 1, 2, or 3 groups independently selected from —OH, C1-C4 alkyl, and C1-C4 alkoxy;
Q 2 is a structure selected from:
each of R 3a and R 3b is independently selected from hydrogen, halogen, —OH, C1-C4 alkoxy, and C1-C4 alkyl; and
R 23 is selected from halogen and —CN.
2. The method of claim 1 , wherein the compound has a structure represented by a formula:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the subject is a mammal.
5. The method of claim 1 , wherein the mammal is a human.
6. The method of claim 1 , further comprising the step of administering to the subject a therapeutically effective amount of carnitine, pantothenate, and/or pantothenic acid.
7. The method of claim 1 , wherein the PA is hereditary.
8. The method of claim 1 , wherein the PA is acquired.
9. A kit for treating propionic acidemia (PA) in a subject in need thereof, comprising:
(a) an effective amount of a compound of claim 1 ; and
(b) at least one agent known to treat the PA,
together with instructions for effective administration.
10. The kit of claim 9 , wherein the at least one agent is carnitine, pantothenate, or pantothenic acid.
11. The kit of claim 9 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
12. The kit of claim 9 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
13. The kit of claim 9 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein Q 1 is CH.
15. The method of claim 1 , wherein R 2 is cyclopropyl.
16. The method of claim 1 , wherein Q 2 is a structure:
17. The method of claim 1 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.