Details

Autor(en) / Beteiligte

• Cox, Christopher D
• Coleman, Paul J
• Breslin, Michael J
• Whitman, David B
• Garbaccio, Robert M
• Fraley, Mark E
• Buser, Carolyn A
• Walsh, Eileen S
• Hamilton, Kelly
• Schaber, Michael D
• Lobell, Robert B
• Tao, Weikang
• Davide, Joseph P
• Diehl, Ronald E
• Abrams, Marc T
• South, Vicki J
• Huber, Hans E
• Torrent, Maricel
• Prueksaritanont, Thomayant
• Li, Chunze
• Slaughter, Donald E
• Mahan, Elizabeth
• Fernandez-Metzler, Carmen
• Yan, Youwei
• Kuo, Lawrence C
• Kohl, Nancy E
• Hartman, George D

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2008-07, Vol.51 (14), p.4239-4252

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 β-fluorination modulated the pK 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.