Design and optimization of a substituted amino propanamide series of renin inhibitors for the treatment of hypertension.
The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.
Chen
Austin
A
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1. austin_chen@merck.com
Bayly
Christopher
C
Bezençon
Olivier
O
Richard-Bildstein
Sylvia
S
Dubé
Daniel
D
Dubé
Laurence
L
Gagné
Sébastien
S
Gallant
Michel
M
Gaudreault
Mireille
M
Grimm
Erich
E
Houle
Robert
R
Lacombe
Patrick
P
Laliberté
Sébastien
S
Lévesque
Jean-François
JF
Liu
Suzanna
S
MacDonald
Dwight
D
Mackay
Bruce
B
Martin
David
D
McKay
Dan
D
Powell
David
D
Remen
L'ubos
L
Soisson
Stephen
S
Toulmond
Sylvie
S
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D012083:Renin; D000092502:Renin Inhibitors