Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Miyazaki, Hiroshi¹  Ikeda, Yousuke¹  Sakurai, Osamu¹  Miyake, Tsutomu¹  Tsubota, Rie¹  Okabe, Jyunko¹  Kuroda, Masataka¹  Hisada, Yutaka¹  Yanagida, Tetsuya¹  Yoneda, Hikaru¹  Tsukumo, Yukihito²  Tokunaga, Shin²  Kawata, Takehisa²  Ohashi, Rikiya¹  Fukuda, Hajime¹  Kojima, Koki¹  Kannami, Ayako¹  Kifuji, Takayuki¹  Sato, Naoya¹  Idei, Akiko¹  Iguchi, Taku¹  Sakairi, Tetsuya¹  Moritani, Yasunori¹ 

[1] Mitsubishi Tanabe Pharma Corp, Aoba ku, 1000 Kamoshida Cho, Yokohama, Kanagawa 2270033, Japan

[2] Kyowa Hakko Kirin Co Ltd, 1188 Shimotogari, Nagaizumi, Shizuoka 4118731, Japan

关键词: Evocalcet;    Calcium-sensing receptor (CaSR);    Allosteric calcium-sensing receptor agonist;    Hyperparathyroidism;    Cinacalcet;   

DOI  :  10.1016/j.bmcl.2018.04.055

来源: Elsevier

【 摘 要 】

The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism. (C) 2018 The Authors. Published by Elsevier Ltd.

【 授权许可】

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