Kinesin spindle protein (KSP) inhibitors. Part 8: Design and synthesis of 1,4-diaryl-4,5-dihydropyrazoles as potent inhibitors of the mitotic kinesin KSP

Anthony J Roecker; Paul J Coleman; Swati P Mercer; John D Schreier; Carolyn A Buser; Eileen S Walsh; Kelly Hamilton; Robert B Lobell; Weikang Tao; Ronald E Diehl; Vicki J South; Joseph P Davide; Nancy E Kohl; Youwei Yan; Lawrence C Kuo; Chunze Li; Carmen Fernandez-Metzler; Elizabeth A Mahan; Thomayant Prueksaritanont; George D Hartman

doi:10.1016/j.bmcl.2007.07.074

Kinesin spindle protein (KSP) inhibitors. Part 8: Design and synthesis of 1,4-diaryl-4,5-dihydropyrazoles as potent inhibitors of the mitotic kinesin KSP

Bioorg Med Chem Lett. 2007 Oct 15;17(20):5677-82. doi: 10.1016/j.bmcl.2007.07.074. Epub 2007 Aug 21.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. anthony_roecker@merck.com

PMID: 17766111
DOI: 10.1016/j.bmcl.2007.07.074

Abstract

Inspired by previous efforts in the pyrazolobenzoxazine class of KSP inhibitors, the design and synthesis of 1,4-diaryl-4,5-dihydropyrazole inhibitors of KSP are described. Crystallographic evidence of binding mode and in vivo potency data is also highlighted.

MeSH terms

Binding Sites
Crystallography, X-Ray
Drug Design*
Humans
Hydrogen / chemistry*
Kinesins / antagonists & inhibitors*
Kinesins / metabolism*
Mitosis / drug effects*
Models, Molecular
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology*
Structure-Activity Relationship

Substances

Pyrazoles
Hydrogen
Kinesins