Agonists of the apelin receptor and methods of use thereof
Provided herein are small molecule agonists of the apelin receptor for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions. The present invention is based on the seminal discovery of a series of potent small molecule agonists of the apelin receptor, which are useful for the treatment of diseases including heart failure, chronic kidney disease, hypertension, and metabolic disorders such as insulin resistance/diabetes and obesity. The compounds disclosed herein are highly specific for the apelin receptor versus the angiotensin II receptor (ATI).
1. A compound of structural Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
A is a substituted aryl, wherein the substituents are selected from the group consisting of halogen, —CN, nitro, amino, alkyl, alkoxy, haloalkoxy and haloalkyl, or A is an optionally substituted heteroaryl, wherein the optional substituents are selected from the group consisting of halogen, —CN, nitro, amino, alkyl, alkoxy, haloalkoxy and haloalkyl;
B is
i) C is
wherein X 3 is S; and
R 9 is optionally substituted aryl, wherein the optional substituents are selected from the group consisting of —CN, nitro, alkyl, haloalkoxy and haloalkyl,
or
ii) C is
Y is O, S, NH, or —N(R 2 );
X 1 is N;
X 2 is CH or N; and
R 2 is selected from the group consisting of aryl, alkyl, and cycloalkyl.
2. The compound of claim 1 , wherein A is substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.
3. The compound of claim 2 , wherein the optional substituents are selected from the group consisting of halogen, —CN, nitro, alkyl, alkoxy, haloalkoxy and haloalkyl.
4. The compound of claim 1 , wherein Y is S, O or NH.
5. The compound of claim 1 , wherein Y is S.
6. The compound of claim 1 , wherein C is
7. The compound of claim 1 , wherein X 2 is N.
8. The compound of claim 7 , wherein C is selected from the group consisting of:
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula III:
10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
11. A compound, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical formulation comprising a compound of structural Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
A is a substituted aryl, wherein the substituents are selected from the group consisting of halogen, —CN, nitro, amino, alkyl, alkoxy, haloalkoxy and haloalkyl, or A is an optionally substituted heteroaryl, wherein the optional substituents are selected from the group consisting of halogen, —CN, nitro, amino, alkyl, alkoxy, haloalkoxy and haloalkyl;
B is
i) C is
wherein X 3 is S or O; and
R 9 is optionally substituted aryl, wherein the optional substituents are selected from the group consisting of halogen, —CN, nitro, alkyl, alkoxy, haloalkoxy and haloalkyl,
or
ii) C is
Y is O, S, NH, or —N(R 2 );
X 1 is N;
X 2 is CH or N; and
R 2 is selected from the group consisting of aryl, alkyl, and cycloalkyl;
and a pharmaceutically acceptable excipient,
wherein the pharmaceutical formulation is a powder.
13. A tablet comprising a compound of structural Formula I, or a pharmaceutically acceptable salt thereof:
wherein:
A is a substituted aryl, wherein the substituents are selected from the group consisting of halogen, —CN, nitro, amino, alkyl, alkoxy, haloalkoxy and haloalkyl, or A is an optionally substituted heteroaryl, wherein the optional substituents are selected from the group consisting of halogen, —CN, nitro, amino, alkyl, alkoxy, haloalkoxy and haloalkyl;
B is
i) C is
wherein X 3 is S or O; and
R 9 is optionally substituted aryl, wherein the optional substituents are selected from the group consisting of halogen, —CN, nitro, alkyl, alkoxy, haloalkoxy and haloalkyl,
or
ii) C is
Y is O, S, NH, or —N(R 2 );
X 1 is N;
X 2 is CH or N; and
R 2 is selected from the group consisting of aryl, alkyl, and cycloalkyl;
and a pharmaceutically acceptable excipient,
wherein the tablet comprises 5 mg to 500 mg of the compound of structural Formula I, or pharmaceutically acceptable salt thereof.
14. The pharmaceutical formulation of claim 12 , wherein A is substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.
15. The pharmaceutical formulation of claim 12 , wherein Y is S; and X 2 is N.
16. The tablet of claim 13 , wherein A is substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.
17. The tablet of claim 13 , wherein Y is S; and X 2 is N.