3,4-Diarylpiperidines as potent renin inhibitors.
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8. lacombepatrick@hotmail.com
Patrick
P
Lacombe
Mélissa
M
Arbour
Renée
R
Aspiotis
Elizabeth
E
Cauchon
Austin
A
Chen
Daniel
D
Dubé
Jean-Pierre
JP
Falgueyret
Pierre-André
PA
Fournier
Michel
M
Gallant
Erich
E
Grimm
Yongxin
Y
Han
Hélène
H
Juteau
Suzanna
S
Liu
Christophe
C
Mellon
Yeeman
Y
Ramtohul
Daniel
D
Simard
René
R
St-Jacques
Gavin Chit
GC
Tsui
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D012083:Renin; D000092502:Renin Inhibitors