Novel and potent calcium-sensing receptor antagonists: Discovery of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate (TAK-075) as an orally active bone anabolic agent

被引：9

作者：

Yoshida, Masato ^{[1
]}

Mori, Akira ^{[1
]}

Morimoto, Shinji ^{[1
]}

Kotani, Etsuo ^{[1
]}

Oka, Masahiro ^{[1
]}

Notoya, Kohei ^{[1
]}

Makino, Haruhiko ^{[1
]}

Ono, Midori ^{[1
]}

Shirasaki, Mikio ^{[1
]}

Tada, Norio ^{[1
]}

Fujita, Hisashi ^{[1
]}

Ban, Junko ^{[1
]}

Ikeda, Yukihiro ^{[1
]}

Kawamoto, Tomohiro ^{[1
]}

Goto, Mika ^{[1
]}

Kimura, Hiroyuki ^{[1
]}

Baba, Atsuo ^{[1
]}

Yasuma, Tsuneo ^{[1
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 06期

关键词：

Orally active; Calcium-sensing receptor antagonists; CaSR; Bone anabolic agents; PTH; TAK-075; PARATHYROID-HORMONE; POSTMENOPAUSAL WOMEN; VERTEBRAL FRACTURES; RANDOMIZED-TRIAL; OSTEOPOROSIS; RISK;

D O I：

10.1016/j.bmc.2011.02.001

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：

The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：1881 / 1894

页数：14