title: Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma.
abstract: The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and associated glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aqueous stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aqueous stable compounds, and addition of solubilizing groups resulted in a set of compounds with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clinical candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clinical trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Harrison
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Zheng Y
authors.initials: ZY
authors.lastname: Almstead
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Hugh
authors.initials: H
authors.lastname: Burgoon
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gardyan
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Goodwin
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Healy
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Ross
authors.initials: R
authors.lastname: Mabon
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Brett
authors.initials: B
authors.lastname: Marinelli
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Samala
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Terry R
authors.initials: TR
authors.lastname: Stouch
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: N Andrew
authors.initials: NA
authors.lastname: Whitlock
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinathan
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Beth
authors.initials: B
authors.lastname: McKnight
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Shuli
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Nita
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Alan G E
authors.initials: AG
authors.lastname: Wilson
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hamman
authors.affiliation: Department of Pharmaceutical Discovery, Department of Drug Metabolism, Pharmacokinetics, and Toxicology and Department of Ophthalmology, Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Rice
authors.affiliation: Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Rawlins
keywords: LIM-kinase; LX7101; ROCK inhibitor; glaucoma; kinase