title: Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP.
abstract: Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. chris_cox@merck.com
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Mariano
authors.forename: David B
authors.initials: DB
authors.lastname: Whitman
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: 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: Vicki J
authors.initials: VJ
authors.lastname: South
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
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: Chunze
authors.initials: C
authors.lastname: Li
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mahan
authors.forename: Bing
authors.initials: B
authors.lastname: Lu
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D000478:Alkylation; D000495:Allosteric Site; D000586:Amination; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006900:Hydroxylation; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008938:Mitosis; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D011720:Pyrazoles; D014867:Water; C031280:pyrazole; D016547:Kinesins