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.
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.
Cox
Christopher D
CD
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. chris_cox@merck.com
Coleman
Paul J
PJ
Breslin
Michael J
MJ
Whitman
David B
DB
Garbaccio
Robert M
RM
Fraley
Mark E
ME
Buser
Carolyn A
CA
Walsh
Eileen S
ES
Hamilton
Kelly
K
Schaber
Michael D
MD
Lobell
Robert B
RB
Tao
Weikang
W
Davide
Joseph P
JP
Diehl
Ronald E
RE
Abrams
Marc T
MT
South
Vicki J
VJ
Huber
Hans E
HE
Torrent
Maricel
M
Prueksaritanont
Thomayant
T
Li
Chunze
C
Slaughter
Donald E
DE
Mahan
Elizabeth
E
Fernandez-Metzler
Carmen
C
Yan
Youwei
Y
Kuo
Lawrence C
LC
Kohl
Nancy E
NE
Hartman
George D
GD
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
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