title: Kinesin spindle protein (KSP) inhibitors. Part 2: the design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP.
abstract: The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s<10nM. Ancillary hERG activity was evaluated for this series of inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_fraley@merck.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: William F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tasber
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandes
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaber
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: South
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Cathy
authors.initials: C
authors.lastname: Shu
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: David C
authors.initials: DC
authors.lastname: Heimbrook
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000473:pathology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000737:chemistry
chemical_list: D011758:Pyrroles; D016547:Kinesins