N-[1-Aryl-2-(1-imidazolo)ethyl]-guanidine derivatives as potent inhibitors of the bovine mitochondrial F1F0 ATP hydrolase.
A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.
Atwal
Karnail S
KS
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA.
Ahmad
Saleem
S
Ding
Charles Z
CZ
Stein
Philip D
PD
Lloyd
John
J
Hamann
Lawrence G
LG
Green
David W
DW
Ferrara
Francis N
FN
Wang
Paulina
P
Rogers
W Lynn
WL
Doweyko
Lidia M
LM
Miller
Arthur V
AV
Bisaha
Sharon N
SN
Schmidt
Joan B
JB
Li
Ling
L
Yost
Kenneth J
KJ
Lan
Hsi-Jung
HJ
Madsen
Cort S
CS
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006146:Guanidines; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases