title: Kinesin spindle protein (KSP) inhibitors. Part 3: synthesis and evaluation of phenolic 2,4-diaryl-2,5-dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueous solubility.
abstract: 2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tasber
authors.forename: Christy M
authors.initials: CM
authors.lastname: Olson
authors.forename: William F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
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: Michael D
authors.initials: MD
authors.lastname: Schaber
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandes
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Vicki 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: Donald E
authors.initials: DE
authors.lastname: Slaughter
authors.forename: Cathy
authors.initials: C
authors.lastname: Shu
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: D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D016547:Kinesins / Q000037:antagonists & inhibitors*; D011355:Prodrugs; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D008941:Spindle Apparatus / Q000737:chemistry; D014867:Water
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D011355:Prodrugs; D011758:Pyrroles; D014867:Water; D016547:Kinesins