title: Discovery of novel dihydrobenzofuran cyclopropane carboxylic acid based calcium sensing receptor antagonists for the treatment of osteoporosis.
abstract: 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.
authors.affiliation: Merck Research Laboratories, Department of Discovery Chemistry, Rahway, NJ 07065, USA. Electronic address: liang_gui-bai@wuxiapptec.com.
authors.forename: Gui-Bai
authors.initials: GB
authors.lastname: Liang
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Huo
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Hank
authors.initials: H
authors.lastname: Wang
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Shaoqiang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Haisheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Department of Bone, Respiratory, Immunology and Endocrinology, Rahway, NJ 07065, USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Wilkinson
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: David
authors.initials: D
authors.lastname: Sutton
authors.affiliation: Bioduro, a PPD Company, Bld E. No. 29, Life Science Park Road, Changping District, Beijing 102206, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, Department of Bone, Respiratory, Immunology and Endocrinology, Rahway, NJ 07065, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Zaller
authors.affiliation: Merck Research Laboratories, Department of Discovery Chemistry, Rahway, NJ 07065, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D003521:Cyclopropanes / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D006207:Half-Life; D010024:Osteoporosis / Q000188:drug therapy* / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D003521:Cyclopropanes; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; C015766:cyclopropanecarboxylic acid
keywords: CaSR-antagonist; Calcium-sensing receptor (CaSR); Cyclopropane carboxylic acid; Osteoporosis; Parathyroid hormone (PTH)