3-(4-(aMinoMethyl)-1-(5-Methyl-7H-pyrrolo[2,3-d]pyriMidin-4-yl)piperidine-4-carboxaMido)phenyl diMethylcarbaMate

Biological Activity

lim-kinases 1 and 2 (limk1 and limk2) regulate cytoskeletal dynamics by phosphorylating and deactivating cofilin, a protein that depolymerizes actin filaments. rock, a kinase upstream of limk in the signaling cascade that regulates actin filament dynamics, are being investigated in the clinic for reduction of iop through relaxation of the trabecular meshwork. lx7101 is a dual lim-kinase and rock inhibitor for the treatment of glaucoma.

in vitro

lx7101 proved significantly more selective for limk2. in addition, lx7101 was screened against a panel of 403 kinases. moderate selectivity was observed in this screen (34 assays including limk2 and rock2 indicated that the kd is most likely <1 μm) [1].

in vivo

at a well-tolerated dose, lx7101 achieved additional reduction of iop compared to the 0.1% formulation and demonstrated a long duration of action, with iop not returning to baseline until more than 8 h postdose. more critically, lx7101 produced a significantly greater reduction of iop than either timolol or latanoprost [1].

IC 50

4.3, 32, 69 and 32 nm for limk2, kimk1, rock1 and rock2, respectivley

References

[1] harrison ba, almstead zy, burgoon h, gardyan m, goodwin nc, healy j, liu y, mabon r, marinelli b, samala l, zhang y, stouch tr, whitlock na, gopinathan s, mcknight b, wang s, patel n, wilson ag, hamman bd, rice ds, rawlins db. discovery and development of lx7101, a dual lim-kinase and rock inhibitor for the treatment of glaucoma. acs med chem lett. 2014 nov 24;6(1):84-8.