Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5563-8. doi: 10.1016/j.bmcl.2012.07.012. Epub 2012 Jul 15.

Abstract

The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.

MeSH terms

  • Animals
  • Benzothiazoles / chemistry*
  • Benzothiazoles / metabolism
  • Benzothiazoles / pharmacokinetics
  • Benzothiazoles / pharmacology*
  • Cathepsin K / antagonists & inhibitors*
  • Cathepsin K / metabolism
  • Dogs
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Nitriles / chemistry*
  • Nitriles / metabolism
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Benzothiazoles
  • Ether-A-Go-Go Potassium Channels
  • Nitriles
  • Cathepsin K