Discovery of novel, potent, and orally bioavailable pyrido[2,3-d][1]benzazepin-6-one antagonists for parathyroid hormone receptor 1

Bioorg Med Chem. 2020 Jun 1;28(11):115524. doi: 10.1016/j.bmc.2020.115524. Epub 2020 Apr 22.

Abstract

Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists.

Keywords: Dibenzazepinone; PTH type 1 receptor (PTHR1) antagonist; Parathyroid hormone (PTH); Pyrido[2,3-d][1]benzazepin-6-one; Scaffold hopping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Male
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Parathyroid Hormone, Type 1 / antagonists & inhibitors*
  • Receptor, Parathyroid Hormone, Type 1 / metabolism
  • Structure-Activity Relationship

Substances

  • PTH1R protein, human
  • Receptor, Parathyroid Hormone, Type 1