IAP binding compounds
IAP binding molecules and compositions including these are disclosed. The IAP binding molecules interact with IAPs (inhibitor of apoptosis proteins) in cells and may be used to modify apoptosis in cells treated with such molecules. Embodiments of these compounds have a K d of less than 0.1 micromolar. Methods of using these IAP binding molecules for therapeutic, diagnostic, and assay purposed are also disclosed.
1. A compound of formula (5)
or a pharmaceutically acceptable salt thereof
where A 1 is H, or methyl;
R 1a is H;
R 1b is methyl or ethyl;
Y is an alkyl, an alkynyl, a cycloalkyl of 3 to 7 carbon atoms, a heteroalkynyl, or optionally substituted versions of these groups, or Y together with R 10 forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Y is linked to R 10 ;
Z 1a and Z 1b are independently an H, hydroxy, alkoxy, or aryloxy;
M is an optionally-substituted alkylene of 1 to 5 carbon atoms;
G is a bond, —O— or —NH— and
R 10 is heteroaryl.
2. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R10 is a substituted heteroaryl.
4. The compound of claim 1 wherein the heteroaryl is selected from the group consisting of benzofurans, benzo[b]thiophene 1-oxide, indoles, 2-thienyls, 3-thienyls, thiophenyls, thiazoyls, pyrazines, and pyridines.
5. The compound of claim 3 wherein the substituted heteroaryl is selected from the group consisting of benzofurans, benzo[b]thiophene 1-oxide, indoles, 2-thienyls, 3-thienyls, thiophenyls, thiazoyls, pyrazines, and pyridines.
6. The compound of claim 5 wherein the substituted heteroaryl is a substituted thiazoyl.
7. A pharmaceutical composition comprising a compound of claim 6 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. A method of treating cancerous cells comprising administering to the cells an TAP binding compound of claim 6 .
9. A method of treating cells comprising:
administering to cells that have a proliferation disorder, wherein the disorder is selected from the group consisting of a cancer or an autoimmune disorder, an amount of the TAP binding compound of claim 6 or a pharmaceutically acceptable salt thereof that reduces the cellular proliferation disorder in the sample of cells.
10. A method of treating cells comprising:
administering to cells that have a proliferation disorder, wherein the disorder is selected from the group consisting of a cancer or an autoimmune disorder, an amount of the TAP binding compound of claim 6 or a pharmaceutically acceptable salt thereof that reduces the cellular proliferation disorder in the sample of cells.
11. A method of treating a cellular proliferative disorder in a patient, wherein the proliferative disorder is selected from the group consisting of a cancer or an autoimmune disorder, the method comprising administering to the patient an TAP binding compound of claim 1 in an amount that ameliorates the cellular proliferative disorder.
12. The method of claim 11 wherein the TAP binding compound is an TAP binding compound of claim 5 .
13. The method of claim 11 wherein the TAP binding compound is an TAP binding compound of claim 6 .
14. The compound of claim 1 or a pharmaceutically acceptable salt wherein
Y is an alkyl or a cycloalkyl of 3 to 7 carbon atoms;
Z 1a and Z 1b are independently —H, hydroxy or alkoxy; and
R 10 is heteroaryl.
15. The compound of claim 14 or a pharmaceutically acceptable salt wherein
M is substituted methylene;
G is —NH—; and
R 10 is substituted thiazoyl.