title: Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer.
abstract: Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. chris_cox@merck.com
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Breslin
authors.forename: David B
authors.initials: DB
authors.lastname: Whitman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
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: Joseph P
authors.initials: JP
authors.lastname: Davide
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Diehl
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
authors.forename: Vicki J
authors.initials: VJ
authors.lastname: South
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.forename: Donald E
authors.initials: DE
authors.lastname: Slaughter
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mahan
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez-Metzler
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D010880:Piperidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C530952:4-(2,5-difluorophenyl)-N-(3-fluoro-1-methylpiperidin-4-yl)-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C470243:KIF11 protein, human; D010880:Piperidines; D011758:Pyrroles; D043823:Taxoids; D016547:Kinesins