Discovery of novel dihydrobenzofuran cyclopropane carboxylic acid based calcium sensing receptor antagonists for the treatment of osteoporosis

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• 作者：Gui-Bai Liang^a ; ^{liang_gui-bai@wuxiapptec.com" class="auth_mail" title="E-mail the corresponding author} ; Changyou Zhou^c ; Xianghong Huo^c ; Hank Wang^c ; Xuelin Yang^c ; Shaoqiang Huang^c ; Haisheng Wang^c ; Hilary Wilkinson^b ; Lusong Luo^c ; Wei Tang^c ; David Sutton^c ; Hong Li^c ; Dennis Zaller^b ; Peter T. Meinke^a
• 关键词：Calcium-sensing receptor (CaSR) ; Parathyroid hormone (PTH) ; Osteoporosis ; CaSR-antagonist ; Cyclopropane carboxylic acid
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：26
• 期：16
• 页码：4077-4080
• 全文大小：1640 K

文摘

In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC₅₀ = 27.6 nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.