Hypoxia-inducible factor 1 (HIF-1) inhibitors
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsKirk R. Gustafson, Martin J. Schnermann, Susanna T. S. Chan, Paresma R. Patel, William D. Figg, James B. McMahon
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Abstract
Embodiments of small molecule inhibitors of hypoxia inducible factor 1 (HIF-1) and pharmaceutical compositions thereof are disclosed. The disclosed compounds suppress HIF-1 activity by inhibiting the interaction between the HIF-1 α subunit and transcriptional co-activator protein p300. Embodiments of methods for making and using the small molecule inhibitors are also disclosed.
Claims22
A compound having a chemical structure according to Formula I or a pharmaceutically acceptable salt thereof
- wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements;
- R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl;
- or
- R1 and R2 together are ═O or ═S;
- each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2;
- m is 0, 1, or 2;
- R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur;
- and
- each Ra independently is hydrogen or alkyl,
- wherein the compound is not a naturally occurring compound.
A pharmaceutical composition comprising:
- (i) at least one compound or pharmaceutically acceptable salt thereof, the compound having a chemical structure according to Formula I or a pharmaceutically acceptable salt thereof
- wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements,
- R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl;
- or R1 and R2 together are ═O or ═S,
- each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2,
- m is 0, 1, or 2,
- R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur, and
- each Ra independently is hydrogen or alkyl;
- and
- (ii) at least one pharmaceutically acceptable carrier.
A method for inhibiting hypoxia-inducible factor 1 (HIF-1) activity, comprising contacting a cell with an effective amount of a compound or pharmaceutically acceptable salt thereof, the compound having a chemical structure according to Formula I
- wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements,
- R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl;
- or R1 and R2 together are ═O or ═S,
- each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2,
- m is 0, 1, or 2,
- R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur, and
- each Ra independently is hydrogen or alkyl.
A method, comprising administering to a subject a therapeutically effective amount of:
- (i) a compound, or a pharmaceutically acceptable salt thereof, the compound having a chemical structure according to Formula I
- wherein each bond depicted as “” is a single or double bond as needed to satisfy valence requirements,
- R1 is —ORa, aryl, heteroaryl, halo, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, —SRa, —COORa, or —N(Ra)2, and R2 is —ORa, —SRa, alicyclic, heteroalicyclic, aryl, or heteroaryl;
- or R1 and R2 together are ═O or ═S,
- each R3 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, —COORa, or —C(O)N(Ra)2,
- m is 0, 1, or 2,
- R4 and R5 together with the carbon atoms to which they are bound define a ring B where the ring B is aryl, heteroaryl, alicyclic, or heteroalicyclic, or R4 and R5 independently are hydrogen, aliphatic, heteroaliphatic, halo, —ORa, —SRa, oxygen, or sulfur, and
- each Ra independently is hydrogen or alkyl, or
- (ii) a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.