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.
Yoshikazu Arai  1 ,  Yohei Kiyotsuka  2 ,  Katsuji Kagechika  2 ,  Tatsuya Nishi  2 ,  Masaharu Inui  2 ,  Masatoshi Nagamochi  2 ,  Kazunori Oyama  2 ,  Masanori Izumi  2
Affiliations
  • 1. End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 32345459 DOI: 10.1016/j.bmc.2020.115524
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.
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