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

[Display omitted] 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=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rat...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-08, Vol.26 (16), p.4077-4080
Main Authors: Liang, Gui-Bai, Zhou, Changyou, Huo, Xianghong, Wang, Hank, Yang, Xuelin, Huang, Shaoqiang, Wang, Haisheng, Wilkinson, Hilary, Luo, Lusong, Tang, Wei, Sutton, David, Li, Hong, Zaller, Dennis, Meinke, Peter T.
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Benzofurans - chemistry
Benzofurans - metabolism
Benzofurans - pharmacokinetics
Benzofurans - therapeutic use
Calcium-sensing receptor (CaSR)
CaSR-antagonist
Cyclopropane carboxylic acid
Cyclopropanes - chemistry
Cyclopropanes - metabolism
Cyclopropanes - pharmacokinetics
Cyclopropanes - therapeutic use
Drug Evaluation, Preclinical
Female
Half-Life
Osteoporosis
Osteoporosis - drug therapy
Osteoporosis - pathology
Parathyroid hormone (PTH)
Parathyroid Hormone - blood
Protein Binding
Rats
Rats, Sprague-Dawley
Receptors, Calcium-Sensing - antagonists & inhibitors
Receptors, Calcium-Sensing - metabolism
Structure-Activity Relationship
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Summary:[Display omitted] 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=27.6nM), 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.06.073