Small molecule bax inhibitors and uses thereof
AssigneesAlbert Einstein College of Medicine, University of Manitoba
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.
Claims21
A method of treating a disease or condition in a subject in which it is desirable to inhibit Bcl-2-associated x-protein (BAX) comprising administering to the subject one or more of the compounds of formula (I) and/or formula (IV) in an amount effective to treat the disease or condition in a subject, wherein formula (I) and formula (IV) have the structure
- wherein
- A is phenyl or a 6-membered heteroaromatic ring having 1, 2 or 3 N atoms in the heteroaromatic ring;
- B is phenyl, or a 6-membered heteroaromatic ring having 1, 2 or 3 N atoms in the heteroaromatic ring;
- or a 6-membered aliphatic ring with up to 3 heteroatoms;
- the dashed line between A and B indicates an optional bond;
- R1 and R2 are independently none, C1-C5 alkyl, F, Cl, Br, I, CN, NO2, NR4, NR42, OR4, CF3, COOH, COOR4, NHR4, OCR4, OCOR4, OR4, SR4, SOR4, or SO2R4;
- X is H, NH2, OH, O, F, Cl, Br, I, CN, SH, NO2, NR4, NR42, OR, CF3, COOH, R4, COOR4, NHR4, OCR4, OCOR4, OR4, SR4, SOR4, or SO2R4;
- wherein the bond between X and the main scaffold is a single bond or a double bond, depending on the definition of X;
- Q is (CH2)mN((CH2)oR5)2, COH, COOH, or CH2NH(CH2)lOH;
- R3 is none, H, C1-C6 alkyl, R4(C═O), or (CH2)lOH;
- R4 is H or C1-C3 alkyl;
- each R5 is independently OH, SH, NR42 or R4;
- Y is O, S, N or CH;
- Z is O, S, NR4, CHR4, S(O)2, C(Me)2 or C(O);
- each 1, m, n, o and p is independently 1-3;
- or a pharmaceutically acceptable salt thereof.
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 or a 6-membered heteroaromatic ring having 1, 2 or 3 N atoms in the heteroaromatic ring;
- B is phenyl, or a 6-membered heteroaromatic ring having 1, 2 or 3 N atoms in the heteroaromatic ring;
- or a 6-membered aliphatic ring with up to 3 heteroatoms;
- the dashed line between A and B indicates an optional bond;
- R1 and R2 are independently none, C1-C5 alkyl, F, Cl, Br, I, CN, NO2, NR4, NR42, OR4, CF3, COOH, COOR4, NHR4, OCR4, OCOR4, OR4, SR4, SOR4, or SO2R4;
- X is H, NH2, OH, O, F, Cl, Br, I, CN, SH, NO2, NR4, NR42, OR, CF3, COOH, R4, COOR4, NHR4, OCR4, OCOR4, OR4, SR4, SOR4, or SO2R4;
- wherein the bond between X and the main scaffold is a single bond or a double bond, depending on the definition of X;
- Q is
- (CH2)mN((CH2)oR5)2, COH, COOH, or CH2NH(CH2)lOH;
- R3 is none, H, C1-C6 alkyl, R4(C═O), or (CH2)pOH;
- R4 is H or C1-C3 alkyl;
- each R5 is independently OH, SH, NR42 or R4;
- Y is O, S, N or CH;
- Z is O, S, NR4, CHR4, S(O)2, C(Me)2 or C(O);
- each l, m, n, o and p is independently 1-3;
- or a pharmaceutically acceptable salt thereof.
A compound having the structure of formula (VII)
- wherein
- A is phenyl or a 6-membered heteroaromatic ring having 1, 2 or 3 N atoms in the heteroaromatic ring;
- B is phenyl, or a 6-membered heteroaromatic ring having 1, 2 or 3 N atoms in the heteroaromatic ring;
- or a 6-membered aliphatic ring with up to 3 heteroatoms;
- R1 and R2 are independently none, C1-C5 alkyl, F, Cl, Br, I, CN, NO2, NR4, NR42, OR4, CF3, COOH, COOR4, NHR4, OCR4, OCOR4, OR4, SR4, SOR4, or SO2R4;
- X is H, NH2, OH, O, F, Cl, Br, I, CN, SH, NO2, NR4, NR42, OR, CF3, COOH, R4, COOR4, NHR4, OCR4, OCOR4, OR4, SR4, SOR4, or SO2R4;
- wherein the bond between X and the main scaffold is a single bond or a double bond, depending on the definition of X;
- Q is
- (CH2)mN((CH2)oOR5)2, COH, COOH, or CH2NH(CH2)lOH;
- R3 is none, H, C1-C6 alkyl, R4(C═O), or (CH2)pOH;
- R4 is H or C1-C3 alkyl;
- each R5 is independently OH, SH, NR42 or R4;
- Y is O, S, N or CH;
- each l, m, n, o and p is independently 1-3;
- or a pharmaceutically acceptable salt thereof.
21-26. (canceled)
Dependencies are inferred from the claim text.