2. Academic Validation
  3. 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)

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.
Yoshikazu Arai 1,  Yohei Kiyotsuka 2,  Masatoshi Nagamochi 2,  Kazunori Oyama 2,  Masanori Izumi 2
Affiliations

Affiliations

  • 1 End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: arai.yoshikazu.mh@daiichisankyo.co.jp.
  • 2 End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 35487102 DOI: 10.1016/j.bmc.2022.116763
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148350
    99.47%, hPTHR1 Antagonist