Discovery of novel PTHR1 antagonists: Design, synthesis, and structure activity relationships

  • Bioorg Med Chem Lett. 2019 Sep 15;29(18):2613-2616. doi: 10.1016/j.bmcl.2019.07.052.
Yoshikazu Arai  1 ,  Yohei Kiyotsuka  2 ,  Kousei Shimada  2 ,  Kazunori Oyama  3 ,  Masanori Izumi  3
Affiliations
  • 1. Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3. Cardiovascular Metabolic Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 31383587 DOI: 10.1016/j.bmcl.2019.07.052
Abstract

The discovery and optimization of a novel series of PTHR1 antagonists are described. Starting from known PTHR1 antagonists, we identified more potent 1,4-benzodiazepin-2-one derivatives by means of a scaffold-hopping approach. The representative compound 23 (DS08210767) exhibited nanomolar-level PTHR1 antagonist activity and potential oral bioavailability in a pharmacokinetic study.

Keywords
1,4-Benzodiazepin-2-one; PTH type 1 receptor (PTHR1) antagonist; Parathyroid hormone (PTH); Scaffold hopping.
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