2. Academic Validation
  3. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer

Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer

  • J Med Chem. 2008 Jul 24;51(14):4239-52. doi: 10.1021/jm800386y.
Christopher D Cox 1,  Paul J Coleman,  Michael J Breslin,  David B Whitman,  Robert M Garbaccio,  Mark E Fraley,  Carolyn A Buser,  Eileen S Walsh,  Kelly Hamilton,  Michael D Schaber,  Robert B Lobell,  Weikang Tao,  Joseph P Davide,  Ronald E Diehl,  Marc T Abrams,  Vicki J South,  Hans E Huber,  Maricel Torrent,  Thomayant Prueksaritanont,  Chunze Li,  Donald E Slaughter,  Elizabeth Mahan,  Carmen Fernandez-Metzler,  Youwei Yan,  Lawrence C Kuo,  Nancy E Kohl,  George D Hartman
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. chris_cox@merck.com
PMID: 18578472 DOI: 10.1021/jm800386y
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.

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