title: In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma.
abstract: A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dosing. Modifications of the 2-(piperazin-1-yl)pyrazine derivatives produced compounds with improved solubility and physicochemical properties. Modifications of the 6-pyrazine substituent led to improvements in in vitro potency. Compound 9 had the best in vitro and in vivo potency of EC50=260 nM with a 30% reduction of IOP in a non-human primate model at a dose of 0.33%.
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Hwang-Hsing
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Abdelmoulah
authors.initials: A
authors.lastname: Namil
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Bryon
authors.initials: B
authors.lastname: Severns
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ward
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Colene
authors.initials: C
authors.lastname: Drace
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Marsha A
authors.initials: MA
authors.lastname: McLaughlin
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Shenouda
authors.initials: S
authors.lastname: Yacoub
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Li
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Patil
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Naj
authors.initials: N
authors.lastname: Sharif
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellberg
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rusinko
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
authors.forename: Iok-Hou
authors.initials: IH
authors.lastname: Pang
authors.affiliation: Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA. Electronic address: kdcom1@yahoo.com.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Combrink
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005901:Glaucoma / Q000188:drug therapy*; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; C520365:Y-39983; D054460:rho-Associated Kinases
keywords: Glaucoma; IOP reduction; Pyrazine; Rho Kinase