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