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

Yoshikazu Arai; Yohei Kiyotsuka; Kousei Shimada; Kazunori Oyama; Masanori Izumi

doi:10.1016/j.bmcl.2019.07.052

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. Epub 2019 Jul 29.

Authors

Yoshikazu Arai¹, Yohei Kiyotsuka², Kousei Shimada², Kazunori Oyama³, Masanori Izumi³

Affiliations

¹ Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: arai.yoshikazu.mh@daiichisankyo.co.jp.
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.

MeSH terms

Benzodiazepinones / chemical synthesis
Benzodiazepinones / chemistry
Benzodiazepinones / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Receptor, Parathyroid Hormone, Type 1 / antagonists & inhibitors*
Receptor, Parathyroid Hormone, Type 1 / metabolism
Structure-Activity Relationship

Substances

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