Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2<i>S</i>)-4-(2,5-Difluorophenyl)-<i>N</i>-[(3<i>R</i>,4<i>S</i>)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-<i>N</i>-methyl-2-phenyl-2,5-dihydro-1<i>H</i>-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer

Abstract

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.