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 . (canceled)
2 . A method of treating methylmalonic acidemia (MMA) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound 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.
3 . The method of claim 2 , wherein the compound has a structure represented by a formula:
or a pharmaceutically acceptable salt thereof.
4 - 5 . (canceled)
6 . The method of claim 2 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
7 - 28 . (canceled)
29 . The method of claim 2 , wherein the subject is a mammal.
30 . The method of claim 2 , wherein the mammal is a human.
31 - 32 . (canceled)
33 . The method of claim 2 , further comprising the step of administering to the subject a therapeutically effective amount of carnitine, pantothenate, and/or pantothenic acid.
34 . The method of claim 2 , wherein the MMA is hereditary.
35 . The method of claim 2 , wherein the MMA is acquired.
36 . A kit for treating methylmalonic acidemia (MMA) in a subject in need thereof, comprising:
(a) an effective amount of a compound of claim 2 ; and
(b) at least one agent known to treat MMA,
together with instructions for effective administration.
37 . (canceled)
38 . The kit of claim 36 , wherein the at least one agent is carnitine, pantothenate, or pantothenic acid.
39 . The kit of claim 36 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
40 . The kit of claim 36 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
41 . The kit of claim 36 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
42 . The method of claim 2 , wherein Q 1 is CH.
43 . The method of claim 2 , wherein R 2 is cyclopropyl.
44 . The method of claim 2 , wherein Q 2 is a structure:
45 . The method of claim 2 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
46 . The method of claim 2 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
47 . The method of claim 2 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.