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Bioorg Med Chem. 2015 May 15;23(10):2424-34. doi: 10.1016/j.bmc.2015.03.052. Epub 2015 Mar 27.

Discovery of novel spiro 1,3,4-thiadiazolines as potent, orally bioavailable and brain penetrant KSP inhibitors.

Author information

1
Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: umar.faruk.mansoor@merck.com.
2
Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
3
Department of Cellular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
4
Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

Abstract

Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models.

KEYWORDS:

1,3,4-Thiadiazolines; Anti-proliferation; Inhibitor; Kinesin spindle protein; Spirocycles

PMID:
25868746
DOI:
10.1016/j.bmc.2015.03.052
[Indexed for MEDLINE]

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