title: Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.
abstract: Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. krista.b.goodman@gsk.com
authors.forename: Krista B
authors.initials: KB
authors.lastname: Goodman
authors.forename: Haifeng
authors.initials: H
authors.lastname: Cui
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dowdell
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Gaitanopoulos
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ivy
authors.forename: Clark A
authors.initials: CA
authors.lastname: Sehon
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stavenger
authors.forename: Gren Z
authors.initials: GZ
authors.lastname: Wang
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: Simon F
authors.initials: SF
authors.lastname: Semus
authors.forename: Christopher
authors.initials: C
authors.lastname: Evans
authors.forename: Harvey E
authors.initials: HE
authors.lastname: Fries
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Jolivette
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: Ross
authors.initials: R
authors.lastname: Bentley
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Doe
authors.forename: Erding
authors.initials: E
authors.lastname: Hu
authors.forename: Dennis
authors.initials: D
authors.lastname: Lee
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D011728:Pyridones; D011743:Pyrimidines; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases