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.
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.
Cox
Christopher D
CD
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. chris_cox@merck.com
Breslin
Michael J
MJ
Whitman
David B
DB
Coleman
Paul J
PJ
Garbaccio
Robert M
RM
Fraley
Mark E
ME
Zrada
Matthew M
MM
Buser
Carolyn A
CA
Walsh
Eileen S
ES
Hamilton
Kelly
K
Lobell
Robert B
RB
Tao
Weikang
W
Abrams
Marc T
MT
South
Vicki J
VJ
Huber
Hans E
HE
Kohl
Nancy E
NE
Hartman
George D
GD
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011437:Propylamines; D011758:Pyrroles; D014867:Water; D005461:Fluorine; D016547:Kinesins