The present invention relates to a family of guanidine-based F1F0-ATPase inhibitors, e.g., mitochondrial F1F0-ATPase inhibitors, methods for their discovery, and their use as therapeutic agents for treating certain disorders.
1. A compound represented by Formula I:
including salts and esters thereof, wherein,
R 1 is imidazolidonyl or a heteroaryl containing at least 1 ring nitrogen atom;
R 2 and R 3 represent independently for each occurrence hydrogen or (C 1 -C 4 )alkyl;
R 4 is
R 5 represents independently for each occurrence hydrogen, halogen, alkyl, haloalkyl, aryl, heteroaryl, —NO 2 , —CN, —C(O)aryl, —C(O)heteroaryl, —C(O)N(R 2 )aryl, or —C(O)N(R 2 )heteroaryl;
R 6 represents independently for each occurrence hydrogen, halogen, alkyl, haloalkyl, alkoxy, aryl, heteroaryl, —NO 2 , —CN, —SO 2 alkyl, or —SO 2 N(alkyl) 2 ;
n is 0, 1, 2, 3, or 4;
m represents independently for each occurrence 1 or 2; and
the stereochemical configuration at a stereocenter in a compound represented by Formula I is R, S, or a mixture thereof.
2. The compound of claim 1 , wherein R 1 is
3. The compound of claim 1 , wherein R 1 is
4. The compound of claim 1 , wherein n is 2, and R 2 and R 3 are hydrogen.
5. The compound of claim 1 , wherein R 4 is
6. The compound of claim 1 , wherein R 6 is
and R 7 represents independently for each occurrence hydrogen, halogen, alkyl, alkoxy, or —CN.
7. The compound of claim 1 , wherein R 5 represents independently for each occurrence halogen, alkyl, haloalkyl, —NO 2 , or —CN.
8. The compound of claim 1 , wherein m is 1.
9. The compound of claim 1 , wherein R 1 is
n is 2, R 2 and R 3 are
hydrogen, and R 4 is
10. The compound of claim 1 , wherein R 1 is
n is 2, R 2 and R 3 are hydrogen, R 4 is
R 5 is halogen, alkyl, haloalkyl, —NO 2 , or —CN, and m is 1.
11. The compound of claim 1 , wherein the compound is one of the following:
12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
13. The compound of claim 1 , wherein the compound has the following formula:
including salts thereof, wherein,
R 1 is a heteroaryl containing at least 1 ring nitrogen atom;
R 2 and R 3 represent independently for each occurrence hydrogen or (C 1 -C 4 )alkyl;
R 4 is
R 5 represents independently for each occurrence hydrogen, halogen, alkyl, haloalkyl, aryl, heteroaryl, —NO 2 , —CN, —C(O)aryl, —C(O)heteroaryl, —C(O)N(R 2 )aryl, or —C(O)N(R 2 )heteroaryl;
R 6 represents independently for each occurrence hydrogen, halogen, alkyl, haloalkyl, alkoxy, aryl, heteroaryl, —NO 2 , —CN, —SO 2 alkyl, or —SO 2 N(alkyl) 2 ;
n is 0, 1, 2, 3, or 4;
m represents independently for each occurrence 1 or 2; and
the stereochemical configuration at a stereocenter in a compound represented by said formula is R, S, or a mixture thereof.
14. The compound of claim 13 , wherein R 5 represents independently for each occurrence halogen, alkyl, or haloalkyl.
15. The compound of claim 14 , wherein R 6 represents independently for each occurrence halogen, alkyl, or haloalkyl.