Small molecule BAX inhibitors and uses thereof
AssigneeAlbert Einstein College of Medicine
InventorsEvripidis Gavathiotis, Richard N. Kitsis, Thomas Peter Garner, Dulguun Amgalan, Lorrie Kirshenbaum, Felix Kopp
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Abstract
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.
Claims17
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;
- R1 and R2 are independently none, C1-C5 alkyl, F, Cl, Br, I, or CF3, wherein at least one of R1 and R2 is present;
- X is NH2, OH, or F, 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;
- m and n are independently 1 or 2;
- provided that when R1 and R2 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 R1 and R2 are each Br, m is 1, n is 1, Y is N, R3 is H, and the dashed line between A and B is a bond, X is not F or OH;
- provided that when R1 and R2 are each F, m is 1, n is 1, Y is N, R3 is H, and the dashed line between A and B is a bond, X is not OH;
- provided that when R1 is none, R2 is none or Br, m is 1, n is 1, Y is N, R3 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.
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;
- R1 and R2 are independently none, C1-C5 alkyl, F, Cl, Br, I, or CF3, wherein in formula (I) at least one of R1 and R2 is present;
- X in Formula (IV) is H, NH2, OH, or F;
- X in Formula (I) is NH2, OH or F,
- wherein the bond between X and the main scaffold is a single bond;
- Q is
- R3 in Formula (IV) is none, H, C1-C6 alkyl, or (CH2)pOH, and R3 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 R1 and R2 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 R1 and R2 are each Br, m is 1, n is 1, Y is N, R3 is H, and the dashed line between A and B is a bond, X is not F or OH;
- provided that when R1 and R2 are each F, m is 1, n is 1, Y is N, R3 is H, and the dashed line between A and B is a bond, X is not OH;
- provided that when R1 is none, R2 is none or Br, m is 1, n is 1, Y is N, R3 is H, and the dashed line between A and B is a bond, X is not OH;
- or a pharmaceutically acceptable salt thereof.
A compound having the structure of formula (VII)
- wherein
- A is phenyl;
- B is phenyl;
- R1 and R2 are independently none, C1-C5 alkyl, F, Cl, Br, I, or CF3, 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, R3 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.
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.
Dependencies are inferred from the claim text.