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

被引:30
作者
Saito, Keiji [1 ]
Nakao, Akira [2 ]
Shinozuka, Tsuyoshi [1 ]
Shimada, Kousei [1 ]
Matsui, Satoshi [2 ]
Oizumi, Kiyoshi [3 ]
Yano, Kazuki [4 ]
Ohata, Keiko [4 ]
Nakai, Daisuke [5 ]
Nagai, Yoko [5 ]
Naito, Satoru [6 ]
机构
[1] Daiichi Sankyo Co Ltd, Lead Discovery & Optimizat Res Labs 1, Shinagawa Ku, Tokyo 1408710, Japan
[2] Daiichi Sankyo Co Ltd, Lead Discovery & Optimizat Res Labs 2, Shinagawa Ku, Tokyo 1408710, Japan
[3] Daiichi Sankyo Co Ltd, Frontier Res Labs, Shinagawa Ku, Tokyo 1408710, Japan
[4] Daiichi Sankyo Co Ltd, Biol Res Labs, Shinagawa Ku, Tokyo 1408710, Japan
[5] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Shinagawa Ku, Tokyo 1408710, Japan
[6] Daiichi Sankyo Co Ltd, R&D Adm & Support Dept, Shinagawa Ku, Tokyo 1408710, Japan
关键词
Osteoporosis; Cell-based screening; Orally active; Bone anabolic agents; Thieno[2,3-b]pyridine; N-Phenyl-homopiperazine; PARATHYROID-HORMONE; OSTEOPOROSIS; THERAPIES; AMINATION;
D O I
10.1016/j.bmc.2013.01.071
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2013 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1628 / 1642
页数:15
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