title: Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma.
abstract: The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocular pressure to baseline levels. The compounds also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and associated glaucoma.
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals, Princeton, New Jersey 08540, USA. bharrison@lexpharma.com
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Harrison
authors.forename: N Andrew
authors.initials: NA
authors.lastname: Whitlock
authors.forename: Michael V
authors.initials: MV
authors.lastname: Voronkov
authors.forename: Zheng Y
authors.initials: ZY
authors.lastname: Almstead
authors.forename: Kun-jian
authors.initials: KJ
authors.lastname: Gu
authors.forename: Ross
authors.initials: R
authors.lastname: Mabon
authors.forename: Michael
authors.initials: M
authors.lastname: Gardyan
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hamman
authors.forename: Jason
authors.initials: J
authors.lastname: Allen
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinathan
authors.forename: Beth
authors.initials: B
authors.lastname: McKnight
authors.forename: Mike
authors.initials: M
authors.lastname: Crist
authors.forename: Yulian
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Courtney
authors.forename: Billie
authors.initials: B
authors.lastname: Key
authors.forename: Julia
authors.initials: J
authors.lastname: Zhou
authors.forename: Nita
authors.initials: N
authors.lastname: Patel
authors.forename: Phil W
authors.initials: PW
authors.lastname: Yates
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Liu
authors.forename: Alan G E
authors.initials: AG
authors.lastname: Wilson
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
authors.forename: Craig E
authors.initials: CE
authors.lastname: Crosson
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Rice
authors.forename: David B
authors.initials: DB
authors.lastname: Rawlins
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005901:Glaucoma / Q000188:drug therapy / Q000503:physiopathology; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects; D054461:Lim Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009798:Ocular Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D006146:Guanidines; D009570:Nitriles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D014508:Urea; D054461:Lim Kinases; C095325:Limk2 protein, mouse