Design and optimization of new piperidines as renin inhibitors.
The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.
Corminboeuf
Olivier
O
Drug Discovery Chemistry & Biochemistry, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.
Bezençon
Olivier
O
Grisostomi
Corinna
C
Remeň
Luboš
L
Richard-Bildstein
Sylvia
S
Bur
Daniel
D
Prade
Lars
L
Hess
Patrick
P
Strickner
Panja
P
Fischli
Walter
W
Steiner
Beat
B
Treiber
Alexander
A
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010880:Piperidines; D000092502:Renin Inhibitors; C465260:Cyp3a2 protein, rat