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

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journal contribution
posted on 08.01.2015, 00:00 by Bryce A. Harrison, Zheng Y. Almstead, Hugh Burgoon, Michael Gardyan, Nicole C. Goodwin, Jason Healy, Ying Liu, Ross Mabon, Brett Marinelli, Lakshman Samala, Yulian Zhang, Terry R. Stouch, N. Andrew Whitlock, Suma Gopinathan, Beth McKnight, Shuli Wang, Nita Patel, Alan G. E. Wilson, Brian D. Hamman, Dennis S. Rice, David B. Rawlins
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.