Identification of a new biaryl scaffold generating potent renin inhibitors.
The discovery and SAR of a series of potent renin inhibitors possessing a novel biaryl scaffold are described herein. Molecular modeling revealed that the cyclopropylamide spacer present in 1 can be replaced by a simple, substituted aromatic ring such as a toluene in 2. The resulting compounds exhibit subnanomolar renin IC(50) and good oral bioavailability in rats.
Lacombe
Patrick
P
Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada.
Aspiotis
Renée
R
Bayly
Christopher
C
Chen
Austin
A
Dubé
Daniel
D
Fortin
Réjean
R
Gallant
Michel
M
Juteau
Hélène
H
Liu
Suzanna
S
McKay
Dan
D
Roy
Patrick
P
Wu
Tom
T
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry; D000818:Animals; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D001632:Bibenzyls; D004791:Enzyme Inhibitors; D012083:Renin; D000092502:Renin Inhibitors