MCT4 inhibitors for treating disease
Provided herein is a method for treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof. The method comprises the step of administering to the subject a compound of structural Formula I and/or a salt thereof. The treatment of the monocarboxylate transporter MCT4-mediated disorder may inhibit activity of MCT4, or a mutant thereof, sometimes with at least a 100-fold selectivity for MCT4 over MCT1.
1. A method for treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof, wherein the treatment selectively inhibits activity of the monocarboxylate transporter MCT4, or a mutant thereof, over the monocarboxylate transporter MCT1, or a mutant thereof, comprising the step of administering to the subject a compound of structural Formula I
and/or a salt thereof, wherein:
A 1 , A 2 , and A 3 are independently chosen from N and C, wherein at least one of A 1 , A 2 , and A 3 is N;
L is chosen from a bond and methylene;
W is chosen from
R 4 and R 5 are independently chosen from C 1 -C 6 alkyl, wherein R 4 and R 5 together comprise no more than 6 carbons;
X is H;
Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, and heteroaryl, any of which may be optionally substituted with one to three R 2 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl; and
Z is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl.
2. The method as recited in claim 1 , wherein the inhibition is at least 100-fold selective for MCT4 over MCT1.
3. The method as recited in claim 1 , wherein
A 1 and A 2 are C; and
A 3 is N.
4. The method as recited in claim 3 , wherein Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl.
5. The method as recited in claim 4 , wherein Y is chosen from phenyl, thienyl, and thiazolyl, any of which may be optionally substituted with one to three R 2 groups each independently chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl.
6. The method as recited in claim 5 , wherein Y is meta-substituted with an R 2 group chosen from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, isopropoxy, isobutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclopropylmethoxy, cyclobutylmethoxy, and cyclopentylmethoxy.
7. The method as recited in claim 3 , wherein:
Y is phenyl, substituted with an R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and
Z is phenyl, substituted with one or two R 3 groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
8. The method as recited in claim 3 , wherein
W is chosen from
and
R 4 and R 5 are independently chosen from alkyl, with R 4 and R 5 together having no more than 6 carbons.
9. The method as recited in claim 8 , wherein R 4 and R 5 are chosen from the following combinations:
R 4 and R 5 are each methyl;
R 4 and R 5 are each ethyl; and
R 4 is methyl and R 5 is ethyl.