title: Kinesin spindle protein (KSP) inhibitors. Part 6: Design and synthesis of 3,5-diaryl-4,5-dihydropyrazole amides as potent inhibitors of the mitotic kinesin KSP.
abstract: 3,5-diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. paul_coleman@merck.com
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: John D
authors.initials: JD
authors.lastname: Schreier
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
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: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Diehl
authors.forename: Vicki J
authors.initials: VJ
authors.lastname: South
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Davide
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kuo
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mahan
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez-Metzler
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Salata
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008938:Mitosis / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; C470243:KIF11 protein, human; D011720:Pyrazoles; D016547:Kinesins