847041-33-2Relevant academic research and scientific papers
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
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.
experimental part, p. 4239 - 4252 (2009/07/04)
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.
MITOTIC KINESIN INHIBITORS
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, (2010/11/24)
The present invention relates to dihydropyrazole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.
A PROCESS FOR THE PREPARATION OF 2,2-DISUBSTITUTED PYRROLES
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Page/Page column 29, (2010/02/14)
The present invention relates to the stereoselective preparation of 2,2-disubstituted-4-carbonatepyrroles from readily available chiral starting materials. Such pyrroles are useful as intermediates in the preparation of 2,2,4-trisubstituted 2,5-dihydropyrroles, that are inhibitors of mitotic kinesins and are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The product of the process of the invention may be illustrated by the Formula (I).
Mitotic kinesin inhibitors
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Page/Page column 32, (2008/06/13)
The present invention relates to dihydropyrrole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention is also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.
