Discovery of novel PTHR1 antagonists: Design,synthesis, and structure activity relationships |
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| Authors: | Yoshikazu Arai Yohei Kiyotsuka Kousei Shimada Kazunori Oyama Masanori Izumi |
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| Institution: | 1. Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;2. Cardiovascular Metabolic Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan |
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| 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. |
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| Keywords: | Corresponding author Parathyroid hormone (PTH) PTH type 1 receptor (PTHR1) antagonist 1 4-Benzodiazepin-2-one Scaffold hopping |
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