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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2008 Jul 24; Vol. 51 (14), pp. 4239-52. Date of Electronic Publication: 2008 Jun 25. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Antineoplastic Agents therapeutic use
Enzyme Inhibitors therapeutic use
Humans
Neoplasms drug therapy
Taxoids therapeutic use
Antineoplastic Agents pharmacology
Enzyme Inhibitors pharmacology
Kinesins antagonists & inhibitors
Neoplasms enzymology
Piperidines pharmacology
Pyrroles pharmacology
Taxoids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 51
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18578472
- Full Text :
- https://doi.org/10.1021/jm800386y