Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP.
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
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
Torrent
Maricel
M
Breslin
Michael J
MJ
Mariano
Brenda J
BJ
Whitman
David B
DB
Coleman
Paul J
PJ
Buser
Carolyn A
CA
Walsh
Eileen S
ES
Hamilton
Kelly
K
Schaber
Michael D
MD
Lobell
Robert B
RB
Tao
Weikang
W
South
Vicki J
VJ
Kohl
Nancy E
NE
Yan
Youwei
Y
Kuo
Lawrence C
LC
Prueksaritanont
Thomayant
T
Slaughter
Donald E
DE
Li
Chunze
C
Mahan
Elizabeth
E
Lu
Bing
B
Hartman
George D
GD
D000478:Alkylation; D000495:Allosteric Site; D000586:Amination; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D006900:Hydroxylation; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008938:Mitosis; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
D011720:Pyrazoles; D014867:Water; C031280:pyrazole; D016547:Kinesins