title: Tetrahydroisoquinoline derivatives as highly selective and potent Rho kinase inhibitors.
abstract: Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC(50) = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.
authors.affiliation: Translational Research Institute and Department of Molecular Therapeutics, The Scripps Research Institute, Florida, Jupiter, Florida 33458, USA.
authors.forename: Xingang
authors.initials: X
authors.lastname: Fang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.forename: Yen Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Yao
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Susan
authors.initials: S
authors.lastname: Khan
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruiz
authors.forename: Thomas
authors.initials: T
authors.lastname: Schröter
authors.forename: Wayne
authors.initials: W
authors.lastname: Grant
authors.forename: Amiee
authors.initials: A
authors.lastname: Weiser
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pocas
authors.forename: Alok
authors.initials: A
authors.lastname: Pachori
authors.forename: Stephan
authors.initials: S
authors.lastname: Schürer
authors.forename: Philip
authors.initials: P
authors.lastname: Lograsso
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C551954:6-methoxy-N-(2-((1-methylpiperidin-4-yl)methoxy)-4-(1H-pyrazol-4-yl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; D000959:Antihypertensive Agents; D007546:Isoquinolines; D011720:Pyrazoles; D044005:Tetrahydroisoquinolines; D054460:rho-Associated Kinases