Discovery of novel dihydrobenzofuran cyclopropane carboxylic acid based calcium sensing receptor antagonists for the treatment of osteoporosis

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4077-80. doi: 10.1016/j.bmcl.2016.06.073. Epub 2016 Jun 29.

Abstract

In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.

Keywords: CaSR-antagonist; Calcium-sensing receptor (CaSR); Cyclopropane carboxylic acid; Osteoporosis; Parathyroid hormone (PTH).

MeSH terms

  • Administration, Oral
  • Animals
  • Benzofurans / chemistry*
  • Benzofurans / metabolism
  • Benzofurans / pharmacokinetics
  • Benzofurans / therapeutic use
  • Cyclopropanes / chemistry
  • Cyclopropanes / metabolism*
  • Cyclopropanes / pharmacokinetics
  • Cyclopropanes / therapeutic use
  • Drug Evaluation, Preclinical
  • Female
  • Half-Life
  • Osteoporosis / drug therapy*
  • Osteoporosis / pathology
  • Parathyroid Hormone / blood
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Calcium-Sensing / antagonists & inhibitors*
  • Receptors, Calcium-Sensing / metabolism
  • Structure-Activity Relationship

Substances

  • Benzofurans
  • Cyclopropanes
  • Parathyroid Hormone
  • Receptors, Calcium-Sensing
  • cyclopropanecarboxylic acid