Lead optimization of pyrido[2,3-d][1]benzazepin-6-one derivatives leading to the discovery of a potent, selective, and orally available human parathyroid hormone receptor 1 (hPTHR1) antagonist (DS69910557)

Bioorg Med Chem. 2022 Jun 15:64:116763. doi: 10.1016/j.bmc.2022.116763. Epub 2022 Apr 22.

Abstract

We report the discovery of a series of novel zwitterionic hPTHR1 antagonists. Optimization of lead compound 2 led to 4-[[1-[4-(2,9-dichloro-5,5-dimethyl-6-oxo-pyrido[2,3-d][1]benzazepin-7-yl)phenyl]-3-fluoro-azetidin-3-yl]methylamino]cyclohexanecarboxylic acid (19e, DS69910557), a compound with excellent potency and selectivity over activity at the human ether-a-go-go-related-gene (hERG) channel. Compound 19e demonstrated in vivo potency to decrease the plasma calcium concentration in rats upon oral administration. 2022 Elsevier Ltd. All rights reserved.

Keywords: Human PTH type 1 receptor (hPTHR1) antagonist; Lead optimization; Parathyroid hormone (PTH); Pyrido[2,3–d][1]benzazepin-6-one; Zwitterionic compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Benzazepines / pharmacology*
  • Humans
  • Rats
  • Receptor, Parathyroid Hormone, Type 1*
  • Structure-Activity Relationship

Substances

  • Benzazepines
  • Receptor, Parathyroid Hormone, Type 1