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ACS Med Chem Lett. 2014 Nov 24;6(1):84-8. doi: 10.1021/ml500367g. eCollection 2015 Jan 8.

Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma.

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Department of Medicinal Chemistry, Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
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.


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.


LIM-kinase; LX7101; ROCK inhibitor; glaucoma; kinase

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