Identification of a new biaryl scaffold generating potent renin inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 19; pp. 5822 - 5826
• Main Authors: Lacombe, Patrick, Aspiotis, Renée, Bayly, Christopher, Chen, Austin, Dubé, Daniel, Fortin, Réjean, Gallant, Michel, Juteau, Hélène, Liu, Suzanna, McKay, Dan, Roy, Patrick, Wu, Tom
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2010; Elsevier
• Subjects: Administration, Oral; Amides - chemistry; Animals; Anti-hypertensive; Antihypertensive agents; Bibenzyls - chemical synthesis; Bibenzyls - chemistry; Bibenzyls - pharmacokinetics; Biological and medical sciences; Cardiovascular system; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Inhibitor; Medical sciences; Pharmacology. Drug treatments; Rats; Renin; Renin - antagonists & inhibitors; Renin - metabolism; Structure-Activity Relationship; Anti-hypertensive; Inhibitor; Renin; Intravenous administration; Rat; Amine; Structure activity relation; Chlorine Organic compounds; Aspartic endopeptidases; Diether; Chemical synthesis; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Bioavailability; In vitro; Peptidases; Vertebrata; Mammalia; Biphenyl derivatives; Animal; Hydrolases; Antihypertensive agent; Carboxamide; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.127

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 our lead compound can be replaced by a simple, substituted aromatic ring such as a toluene. The resulting compounds exhibit subnanomolar renin IC 50 and good oral bioavailability in rats. 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.