Optimization of orally bioavailable alkyl amine renin inhibitors.
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
Xu
Zhenrong
Z
Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.
Cacatian
Salvacion
S
Yuan
Jing
J
Simpson
Robert D
RD
Jia
Lanqi
L
Zhao
Wei
W
Tice
Colin M
CM
Flaherty
Patrick T
PT
Guo
Joan
J
Ishchenko
Alexey
A
Singh
Suresh B
SB
Wu
Zhongren
Z
McKeever
Brian M
BM
Scott
Boyd B
BB
Bukhtiyarov
Yuri
Y
Berbaum
Jennifer
J
Mason
Jennifer
J
Panemangalore
Reshma
R
Cappiello
Maria Grazia
MG
Bentley
Ross
R
Doe
Christopher P
CP
Harrison
Richard K
RK
McGeehan
Gerard M
GM
Dillard
Lawrence W
LW
Baldwin
John J
JJ
Claremon
David A
DA
D000284:Administration, Oral; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000097:blood / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000588:Amines; D002219:Carbamates; D004791:Enzyme Inhibitors; D010880:Piperidines; D012083:Renin; D000092502:Renin Inhibitors