Discovery and structure-activity relationship of thienopyridine derivatives as bone anabolic agents.

Keiji Saito, Akira Nakao, Tsuyoshi Shinozuka, Kousei Shimada, Satoshi Matsui, Kiyoshi Oizumi, Kazuki Yano, Keiko Ohata, Daisuke Nakai, Yoko Nagai, Satoru Naito

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

Bioorganic & medicinal chemistry 2013 Apr 1

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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. Copyright © 2013 Elsevier Ltd. All rights reserved.

Citation

Keiji Saito, Akira Nakao, Tsuyoshi Shinozuka, Kousei Shimada, Satoshi Matsui, Kiyoshi Oizumi, Kazuki Yano, Keiko Ohata, Daisuke Nakai, Yoko Nagai, Satoru Naito. Discovery and structure-activity relationship of thienopyridine derivatives as bone anabolic agents. Bioorganic & medicinal chemistry. 2013 Apr 1;21(7):1628-42