N,N-dimethyl-carbamic acid, 3-[[[4-(aminomethyl)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]carbonyl]amino]phenyl ester, monohydrochloride

Description

LX7101 HCl is a pyrrolopyrimidine-based, topically-delivered inhibitor of LIM domain kinase 2 (LIMK2), a kinase associated with the regulation of intraocular pressure. It is also a ROCK inhibitor used for the treatment of glaucoma. LX7101 acts by enhancing fluid outflow through the trabecular meshwork of the eye. Preclinical studies indicate that LX7101 significantly reduced intraocular pressure in both mouse and monkey models. The latest stage of development for LX7101 was a randomized, double-blind, placebo-controlled Phase 1/2a trial for patients with open angle glaucoma or ocular hypertension.

Uses

LX7101 monohydrochloride is a potent LIM-kinase, ROCK and PKA inhibitor with IC50s of 24 nM, 1.6 nM, 10 nM and <1 nM for LIMK1, LIMK2, ROCK2 and PKA, respectively. LX7101 monohydrochloride proves significantly selective for LIMK2 with IC50 values of 4.3 nM and 32 nM for LIMK2 and LIMK1 at 2 μM ATP, respectively. LX7101 monohydrochloride has the potential for ocular hypertension and associated glaucoma research[1][2].

in vivo

IC 50

LIMK1: 24 nM (IC₅₀); LIMK2: 1.6 nM (IC₅₀); ROCK2: 10 nM (IC₅₀); PKA: <1 nM (IC₅₀)

References

[1] Boland S, et al. Design, synthesis and biological characterization of selective LIMK inhibitors. Bioorganic & Medicinal Chemistry Letters (2015), 25(18), 4005-4010. DOI:10.1016/j.bmcl.2015.07.009
[2] Harrison BA, et al. Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma. ACS Medicinal Chemistry Letters (2015), 6(1), 84-88. DOI:10.1021/ml500367g