Design and optimization of renin inhibitors: Orally bioavailable alkyl amines.
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Tice
Colin M
CM
Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA. ctice@vitaerx.com
Xu
Zhenrong
Z
Yuan
Jing
J
Simpson
Robert D
RD
Cacatian
Salvacion T
ST
Flaherty
Patrick T
PT
Zhao
Wei
W
Guo
Joan
J
Ishchenko
Alexey
A
Singh
Suresh B
SB
Wu
Zhongren
Z
Scott
Boyd B
BB
Bukhtiyarov
Yuri
Y
Berbaum
Jennifer
J
Mason
Jennifer
J
Panemangalore
Reshma
R
Cappiello
Maria Grazia
MG
Müller
Dominik
D
Harrison
Richard K
RK
McGeehan
Gerard M
GM
Dillard
Lawrence W
LW
Baldwin
John J
JJ
Claremon
David A
DA
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001794:Blood Pressure; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D008744:Methylamines; D012083:Renin; D000092502:Renin Inhibitors