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

Umar Faruk Mansoor; Angie R Angeles; Chaoyang Dai; Liping Yang; Dilrukshi Vitharana; Andrea D Basso; Kimberly Gray; Huadong Tang; Ming Liu; Lianzhu Liang; Omaira Allbritton; M Arshad Siddiqui

doi:10.1016/j.bmc.2015.03.052

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

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

Affiliations

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.

PMID: 25868746
DOI: 10.1016/j.bmc.2015.03.052

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.

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Biomarkers / metabolism
Blood-Brain Barrier / drug effects
Brain Neoplasms / drug therapy*
Brain Neoplasms / genetics
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Line, Tumor
Dogs
Drug Discovery
HCT116 Cells
Histones / metabolism
Humans
Kinesins / antagonists & inhibitors*
Kinesins / genetics
Kinesins / metabolism
Male
Mice
Permeability
Piperidines / chemistry
Pyrimidines / chemistry
Pyrroles / chemistry
Rats
Spiro Compounds / chemical synthesis*
Spiro Compounds / pharmacokinetics
Spiro Compounds / pharmacology
Thiadiazoles / chemical synthesis*
Thiadiazoles / pharmacokinetics
Thiadiazoles / pharmacology
Thiones / chemistry
Tubulin Modulators / chemical synthesis*
Tubulin Modulators / pharmacokinetics
Tubulin Modulators / pharmacology
Xenograft Model Antitumor Assays

Substances

4-(2,5-difluorophenyl)-N-(3-fluoro-1-methylpiperidin-4-yl)-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide
Antineoplastic Agents
Biomarkers
Histones
KIF11 protein, human
Piperidines
Pyrimidines
Pyrroles
Spiro Compounds
Thiadiazoles
Thiones
Tubulin Modulators
monastrol
Kinesins