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

被引：140

作者：

Cox, Christopher D. ^{[1
]}

Coleman, Paul J. ^{[1
]}

Breslin, Michael J. ^{[1
]}

Whitman, David B. ^{[1
]}

Garbaccio, Robert M. ^{[1
]}

Fraley, Mark E. ^{[1
]}

Buser, Carolyn A. ^{[2
]}

Walsh, Eileen S. ^{[2
]}

Hamilton, Kelly ^{[2
]}

Schaber, Michael D. ^{[2
]}

Lobell, Robert B. ^{[2
]}

Tao, Weikang ^{[2
]}

Davide, Joseph P. ^{[2
]}

Diehl, Ronald E. ^{[2
]}

Abrams, Marc T. ^{[2
]}

South, Vicki J. ^{[2
]}

Huber, Hans E. ^{[2
]}

Torrent, Maricel ^{[3
]}

Prueksaritanont, Thomayant ^{[4
]}

Li, Chunze ^{[4
]}

Slaughter, Donald E. ^{[4
]}

Mahan, Elizabeth ^{[4
]}

Fernandez-Metzler, Carmen ^{[4
]}

Yan, Youwei ^{[5
]}

Kuo, Lawrence C. ^{[5
]}

Kohl, Nancy E. ^{[2
]}

Hartman, George D. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

[5] Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 14期

关键词：

D O I：

10.1021/jm800386y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 pK(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.

引用

页码：4239 / 4252

页数：14

共 49 条

[1] Mitotic kinesins: Prospects for antimitotic drug discovery [J].

Bergnes, G ;

Brejc, K ;

Belmont, L .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (02) :127-145

[2] Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes [J].

Cerny, MA ;

Hanzlik, RP .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2005, 436 (02) :265-275

[3] Timeline - Chemotherapy and the war on cancer [J].

Chabner, BA ;

Roberts, TG .

NATURE REVIEWS CANCER, 2005, 5 (01) :65-72

[4] Kinesin spindle protein (KSP) inhibitors. Part 6: Design and synthesis of 3,5-diaryl-4,5-dihydropyrazole amides as potent inhibitors of the mitotic kinesin KSP [J].

Coleman, Paul J. ;

Schreler, John D. ;

Cox, Christopher D. ;

Fraley, Mark E. ;

Garbaccio, Robert M. ;

Buser, Carolyn A. ;

Walsh, Eileen S. ;

Hamilton, Kelly ;

Lobell, Robert B. ;

Rickert, Keith ;

Tao, Weikang ;

Diehl, Ronald E. ;

South, Vicki J. ;

Davide, Joseph P. ;

Kohl, Nancy E. ;

Yan, Youwei ;

Kuo, Lawrence ;

Prueksaritanont, Thomayant ;

Li, Chunze ;

Mahan, Elizabeth A. ;

Fernandez-Metzler, Carmen ;

Salata, Joseph J. ;

Hartman, George D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (19) :5390-5395

[5] Taxanes in breast cancer: An update [J].

Conlin A.K. ;

Seidman A.D. .

Current Oncology Reports, 2007, 9 (1) :22-30

[6] 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 [J].

Cox, CD ;

Torrent, M ;

Breslin, MJ ;

Mariano, BJ ;

Whitman, DB ;

Coleman, PJ ;

Buser, CA ;

Walsh, ES ;

Hamilton, K ;

Schaber, MD ;

Lobell, RB ;

Tao, WK ;

South, VJ ;

Kohl, NE ;

Yan, YW ;

Kuo, LC ;

Prueksaritanont, T ;

Slaughter, DE ;

Li, CZ ;

Mahan, E ;

Lu, B ;

Hartman, GD .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (12) :3175-3179

[7] Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP [J].

Cox, CD ;

Breslin, MJ ;

Brenda, JM ;

Coleman, PJ ;

Buser, CA ;

Walsh, ES ;

Hamilton, K ;

Huber, HE ;

Kohl, NE ;

Torrent, M ;

Yan, YW ;

Kuo, LC ;

Hartman, GD .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (08) :2041-2045

[8] 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 β-fluorination to overcome cellular efflux by P-glycoprotein [J].

Cox, Christopher D. ;

Breslin, Michael J. ;

Whitman, David B. ;

Coleman, Paul J. ;

Garbaccio, Robert M. ;

Fraley, Mark E. ;

Zrada, Matthew M. ;

Buser, Carolyn A. ;

Walsh, Eileen S. ;

Hamilton, Kelly ;

Lobell, Robert B. ;

Tao, Weikang ;

Abrams, Marc T. ;

South, Vicki J. ;

Huber, Hans E. ;

Kohl, Nancy E. ;

Hartman, George D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (10) :2697-2702

[9] Mitotic phosphorylation of histone H3: Spatio-temporal regulation by mammalian aurora kinases [J].

Crosio, C ;

Fimia, GM ;

Loury, R ;

Kimura, M ;

Okano, Y ;

Zhou, HY ;

Sen, S ;

Allis, CD ;

Sassone-Corsi, P .

MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (03) :874-885

[10]

Dutcher JP, 2000, J CLIN PHARMACOL, V40, P1079

← 1 2 3 4 5 →