Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Abstract

The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity, and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (> 400-fold), potent inhibition of cofilin phosphorylation in A7r5,PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥ 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers

“…LIMKs are considered as emerging targets for cancer therapy (21), and an increasing number of inhibitors is reported in the literature (2,(22)(23)(24)(25)(26)(27)(28). Among these inhibitors, few, if any, fulfill the three criteria that are important for in vivo experiments, that is, high selectivity, complete characterization of the effects on both actin and microtubule dynamics, and knowledge of toxicity on animals.…”

Design, synthesis and biological characterization of selective LIMK inhibitors

“…11 In spite of those multiple potential indications, the number of reported LIMK inhibitor series remains modest, in comparison to more common kinase targets. The most potent examples of LIMK inhibitors reported to date are based on pyrrolopyrimidines 6,7,12,13 or 2-aminothiazole scaffolds. 14-17 A series of non-competitive (Type III) LIMK inhibitors was also recently reported.…”

“…7 Selectivity between LIMK and ROCK can however be achieved, as demonstrated by a recent series of bis-aryl urea derivatives incorporating the pyrrolopyrimidine scaffold but displaying strong selectivity versus ROCK. 13 Herein, we report the synthesis and evaluation of new analogs of LX-7101, alongside with the identification and biological characterization of a selective LIMK inhibitor. Our synthetic efforts were focused on modulation of the amine, of the pyrrolopyrimidine scaffold, and on replacement of the carbamate moiety of LX-7101.…”

“…Several of our findings are in line with those recently reported for bis-aryl urea LIMK inhibitors. 13 However, some diverging observations can be made with respect to the effect of methyl groups. We here found that a 5-Me substitution on the pyrrolopyrimidine had little or no effect on LIMK1 (3 vs 13, 4 vs 17), but could affect selectivity versus ROCK2 and PKA, depending on the amine present on the piperidinyl moiety.…”

“…7,8,14 However, those results were generated in animal models featuring a higher IOP baseline than for NZW rabbits. For instance, a baseline IOP of 28 mmHg was reported for rats used in the evaluation of bis-aryl urea LIMK inhibitors; 13 and LX-7101 was evaluated in a dexamethasone-induced ocular hypertensive mouse model. 7 This point might be of importance, because ROCK inhibitors (and by extension LIMK inhibitors) normally target the trabecular outflow of aqueous humor; 26 which is a pressure-dependent contribution.…”