title: Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. robert.a.stavenger@gsk.com
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stavenger
authors.forename: Haifeng
authors.initials: H
authors.lastname: Cui
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dowdell
authors.forename: Robert G
authors.initials: RG
authors.lastname: Franz
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Gaitanopoulos
authors.forename: Krista B
authors.initials: KB
authors.lastname: Goodman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hilfiker
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ivy
authors.forename: Jack D
authors.initials: JD
authors.lastname: Leber
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
authors.forename: Hye-Ja
authors.initials: HJ
authors.lastname: Oh
authors.forename: Andrew Q
authors.initials: AQ
authors.lastname: Viet
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xu
authors.forename: Guosen
authors.initials: G
authors.lastname: Ye
authors.forename: Daohua
authors.initials: D
authors.lastname: Zhang
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Jolivette
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: Simon F
authors.initials: SF
authors.lastname: Semus
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Elkins
authors.forename: Robert B
authors.initials: RB
authors.lastname: Kirkpatrick
authors.forename: Edward
authors.initials: E
authors.lastname: Dul
authors.forename: Sanjay S
authors.initials: SS
authors.lastname: Khandekar
authors.forename: Tracey
authors.initials: T
authors.lastname: Yi
authors.forename: David K
authors.initials: DK
authors.lastname: Jung
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
authors.forename: Gary K
authors.initials: GK
authors.lastname: Smith
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Doe
authors.forename: Ross
authors.initials: R
authors.lastname: Bentley
authors.forename: Zunxuan X
authors.initials: ZX
authors.lastname: Chen
authors.forename: Erding
authors.initials: E
authors.lastname: Hu
authors.forename: Dennis
authors.initials: D
authors.lastname: Lee
mesh_terms: 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
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010069:Oxadiazoles; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases