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.
Umar Faruk Mansoor  1 ,  Angie R Angeles  2 ,  Chaoyang Dai  2 ,  Liping Yang  2 ,  Dilrukshi Vitharana  2 ,  Andrea D Basso  3 ,  Kimberly Gray  3 ,  Huadong Tang  4 ,  Ming Liu  3 ,  Lianzhu Liang  3 ,  Omaira Allbritton  3 ,  M Arshad Siddiqui  2
Affiliations
  • 1. Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: [email protected].
  • 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.