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

Bioorg Med Chem. 2011 Mar 15;19(6):1881-94. doi: 10.1016/j.bmc.2011.02.001.

Masato Yoshida ¹, Akira Mori, Shinji Morimoto, Etsuo Kotani, Masahiro Oka, Kohei Notoya, Haruhiko Makino, Midori Ono, Mikio Shirasaki, Norio Tada, Hisashi Fujita, Junko Ban, Yukihiro Ikeda, Tomohiro Kawamoto, Mika Goto, Hiroyuki Kimura, Atsuo Baba, Tsuneo Yasuma

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Affiliation

1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohomachi, Yodogawa-ku, Osaka 532-8686, Japan.

PMID: 21353570 DOI: 10.1016/j.bmc.2011.02.001

Abstract

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.

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