Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6625-8. doi: 10.1016/j.bmcl.2013.10.050. Epub 2013 Oct 31.

Abstract

A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.

Keywords: 1,2,4-Thiadiazoles; Calcimimetics; Metabolite ID; Positive allosteric modulators; Time dependent inhibition.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Half-Life
  • Hyperparathyroidism, Secondary / drug therapy*
  • Hyperparathyroidism, Secondary / metabolism
  • Hyperparathyroidism, Secondary / pathology
  • Male
  • Parathyroid Hormone / metabolism
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Calcium-Sensing / chemistry
  • Receptors, Calcium-Sensing / metabolism
  • Thiazoles / chemistry*
  • Thiazoles / pharmacokinetics
  • Thiazoles / therapeutic use*
  • Urea / analogs & derivatives*

Substances

  • Parathyroid Hormone
  • Receptors, Calcium-Sensing
  • Thiazoles
  • Urea