Small molecule BAX inhibitors and uses thereof
Compounds, compositions and method of using these compounds are disclosed for treating a disease or disorder in which it is desirable to inhibit BAX, such as a cardiovascular disease or disorder.
1 . A method of treating a disease or condition associated with dysregulation of apoptosis mediated by Bcl-2-associated x-protein (BAX) comprising administering to the subject one or more of the compounds of formula (I) in an amount effective to inhibit the BAX and to treat the disease or condition in a subject, wherein formula (I) has the
structure
wherein
A is phenyl;
B is phenyl;
the dashed line between A and B indicates an optional bond;
R 1 and R 2 are independently none, C1-C5 alkyl, F, Cl, Br, I, or CF 3 , wherein at least one of R 1 and R 2 is present;
X is NH 2 , OH, or F, wherein the bond between X and the main scaffold is a single bond;
Q is
R 3 is none, H, or C1-C6 alkyl;
Y is O or N;
m and n are independently 1 or 2;
provided that when R 1 and R 2 are each Cl, m is 1, n is 1, X is OH, and the dashed line between A and B is a bond, then Y is O and R 3 is none;
provided that when R 1 and R 2 are each Br, m is 1, n is 1, Y is N, R 3 is H, and the dashed line between A and B is a bond, X is not F or OH;
provided that when R 1 and R 2 are each F, m is 1, n is 1, Y is N, R 3 is H, and the dashed line between A and B is a bond, X is not OH;
provided that when R 1 is none, R 2 is none or Br, m is 1, n is 1, Y is N, R 3 is H, and the dashed line between A and B is a bond, X is not OH;
or a pharmaceutically acceptable salt thereof,
wherein the disease or condition is selected from the group consisting of Huntington's disease, retinitis pigmentosa, arthritis, lupus, Crohn's disease, and multiple sclerosis.
2 . The method of claim 1 , wherein there is no bond between A and B.
3 . The method of claim 1 , wherein X is OH or F.
4 . The method of claim 1 , wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
5 . The method of claim 1 , wherein the one or more compounds is administered in an amount effective to inhibit BAX in a subject.
6 . The method of claim 1 , where R1 and/or R2 are in the para position with respect to the bond to the N atom.
7 . The method of claim 1 , wherein the subject is human.
8 . A method of inhibiting Bcl-2-associated x-protein (BAX) in a subject comprising contacting the BAX with one or more of the compounds of formula (I) and/or formula (IV) in an amount effective to inhibit BAX, wherein formula (I) and formula (IV) have the structure
wherein
A is phenyl;
B is phenyl;
the dashed line between A and B indicates an optional bond;
R 1 and R 2 are independently none, C1-C5 alkyl, F, Cl, Br, I, or CF 3 , wherein in formula (I) at least one of R 1 and R 2 is present;
X in Formula (IV) is H, NH 2 , OH, or F;
X in Formula (I) is NH 2 , OH or F,
wherein the bond between X and the main scaffold is a single bond;
Q is
R 3 in Formula (IV) is none, H, C1-C6 alkyl, or (CH 2 )pOH, and R 3 in Formula (I) is none, H or C1-C6 alkyl;
Y is O or N;
Z is O or S;
each of m, n, and p is independently 1 or 2;
provided that when R 1 and R 2 are each Cl, m is 1, n is 1, X is OH, and the dashed line between A and B is a bond, then Y is O and R3 is none;
provided that when R 1 and R 2 are each Br, m is 1, n is 1, Y is N, R 3 is H, and the dashed line between A and B is a bond, X is not F or OH;
provided that when R 1 and R 2 are each F, m is 1, n is 1, Y is N, R 3 is H, and the dashed line between A and B is a bond, X is not OH;
provided that when R 1 is none, R 2 is none or Br, m is 1, n is 1, Y is N, R 3 is H, and the dashed line between A and B is a bond, X is not OH;
or a pharmaceutically acceptable salt thereof.
9 . The method of claim 8 , wherein the subject has a disease or condition selected from the group consisting of Huntington's disease, retinitis pigmentosa, arthritis, lupus, Crohn's disease, and multiple sclerosis.
10 . The method of claim 8 , wherein there is no bond between A and B in the compound of formula (I).
11 . The method of claim 8 , wherein the compound of formula (IV) is a compound of formula (V)
or a pharmaceutically acceptable salt thereof, wherein Z is S.
12 . The method of claim 8 , wherein R1 in the compound of formula (I) or R 2 in the compound of formula (IV) and/or R 2 in the compound of formula (I) or R 3 in the compound of formula (IV), are in the para position with respect to the bond next to the N atom.
13 . The method of claim 8 , wherein the subject is human.
14 . A compound having the structure of formula (VII)
wherein
A is phenyl;
B is phenyl;
R 1 and R 2 are independently none, C1-C5 alkyl, F, Cl, Br, I, or CF 3 , wherein the bond between X and the main scaffold is a single bond;
Q is
R3 is none, H, or C1-C6 alkyl;
Y is O or N;
each of m, n, and p is independently 1;
provided that when R1 and R2 are each Br, m is 1, n is 1, Y is N, R 3 is H, and the dashed line between A and B is a bond, X is not F or OH;
or a pharmaceutically acceptable salt thereof.
15 . The method of claim 8 , wherein the compound of formula (IV) is
16 . A method for inhibiting Bcl-2-associated x-protein (BAX) in a subject, comprising contacting the BAX with a compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
17 . The method of claim 16 , wherein the subject has been diagnosed with a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, retinitis pigmentosa, spinal muscular atrophy, amyotrophic lateral sclerosis, arthritis, lupus, Crohn's disease, and multiple sclerosis.