Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity.
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
Stavenger
Robert A
RA
Department of Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. robert.a.stavenger@gsk.com
Cui
Haifeng
H
Dowdell
Sarah E
SE
Franz
Robert G
RG
Gaitanopoulos
Dimitri E
DE
Goodman
Krista B
KB
Hilfiker
Mark A
MA
Ivy
Robert L
RL
Leber
Jack D
JD
Marino
Joseph P
JP
Oh
Hye-Ja
HJ
Viet
Andrew Q
AQ
Xu
Weiwei
W
Ye
Guosen
G
Zhang
Daohua
D
Zhao
Yongdong
Y
Jolivette
Larry J
LJ
Head
Martha S
MS
Semus
Simon F
SF
Elkins
Patricia A
PA
Kirkpatrick
Robert B
RB
Dul
Edward
E
Khandekar
Sanjay S
SS
Yi
Tracey
T
Jung
David K
DK
Wright
Lois L
LL
Smith
Gary K
GK
Behm
David J
DJ
Doe
Christopher P
CP
Bentley
Ross
R
Chen
Zunxuan X
ZX
Hu
Erding
E
Lee
Dennis
D
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010069:Oxadiazoles; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases