title: Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by beta-fluorination to overcome cellular efflux by P-glycoprotein.
abstract: Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. chris_cox@merck.com
authors: Christopher D
authors: CD
authors: Cox
authors: Michael J
authors: MJ
authors: Breslin
authors: David B
authors: DB
authors: Whitman
authors: Paul J
authors: PJ
authors: Coleman
authors: Robert M
authors: RM
authors: Garbaccio
authors: Mark E
authors: ME
authors: Fraley
authors: Matthew M
authors: MM
authors: Zrada
authors: Carolyn A
authors: CA
authors: Buser
authors: Eileen S
authors: ES
authors: Walsh
authors: Kelly
authors: K
authors: Hamilton
authors: Robert B
authors: RB
authors: Lobell
authors: Weikang
authors: W
authors: Tao
authors: Marc T
authors: MT
authors: Abrams
authors: Vicki J
authors: VJ
authors: South
authors: Hans E
authors: HE
authors: Huber
authors: Nancy E
authors: NE
authors: Kohl
authors: George D
authors: GD
authors: Hartman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D001692:Biological Transport; D003599:Cytoskeleton; D005461:Fluorine / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012995:Solubility; D014867:Water
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011437:Propylamines; D011758:Pyrroles; D014867:Water; D005461:Fluorine; D016547:Kinesins