title: Discovery and structure-activity relationship of thienopyridine derivatives as bone anabolic agents.
abstract: A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day.
authors: Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. saito.keiji.e2@daiichisankyo.co.jp
authors: Keiji
authors: K
authors: Saito
authors: Akira
authors: A
authors: Nakao
authors: Tsuyoshi
authors: T
authors: Shinozuka
authors: Kousei
authors: K
authors: Shimada
authors: Satoshi
authors: S
authors: Matsui
authors: Kiyoshi
authors: K
authors: Oizumi
authors: Kazuki
authors: K
authors: Yano
authors: Keiko
authors: K
authors: Ohata
authors: Daisuke
authors: D
authors: Nakai
authors: Yoko
authors: Y
authors: Nagai
authors: Satoru
authors: S
authors: Naito
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D045930:Anabolic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D055808:Drug Discovery; D005260:Female; D006801:Humans; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism; D010052:Ovariectomy; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D058924:Thienopyridines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D045930:Anabolic Agents; D058924:Thienopyridines; D000469:Alkaline Phosphatase