Synthesis and characterization of 2,4-diaryl-2,5-dihydropyrrole-2-(3'phenol) inhibitors of the mitotic kinesin KSP

MEDI 111

Robert M. Garbaccio1, Edward S. Tasber1, Mark E. Fraley, mark_fraley@merck.com1, George D. Hartman1, Robert B. Lobell2, Carolyn A. Buser2, Weikang Tao2, Hans E. Huber2, Nancy E. Kohl2, Youwei Yan3, Lawrence C. Kuo3, Maricel Torrent, maricel_torrent@merck.com4, Thomayant Prueksaritanont5, Cathy Shu6, and Donald Slaughter6. (1) Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, P.O. Box 4, WP 14-1, West Point, PA 19486-0004, (2) Department of Cancer Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, (3) Department of Structural Biology, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, (4) Molecular Systems, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, (5) Department of Molecular Endocrinology, and Department of Drug Metabolism, Merck Research Laboratories, Sumeytown Pike, West Point, PA 19486, (6) Department of Drug Metabolism, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486
Kinesin Spindle Protein (KSP) is a mitotic kinesin which plays an essential role in the formation and maintenance of the mitotic spindle required during mitosis. Inhibition of KSP causes the collapse of the bipolar spindle, which subsequently induces mitotic arrest and apoptosis. Therefore, small molecule KSP inhibitors are regarded as potential, novel chemotherapeutics. This presentation covers the evolution of phosphate prodrug forms (e.g. Compound 1) of 2,4-diaryl-2,5-dihydropyrrole-2-(3'phenol) KSP inhibitors. Issues including in vitro KSP inhibition, IKr potassium channel activity, and in vivo xenograph tumor studies are addressed. Synthesis and SAR of the phenol-bearing KSP inhibitors will be presented.

 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006