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 |
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Authors: | Yoshida Masato Mori Akira Morimoto Shinji Kotani Etsuo Oka Masahiro Notoya Kohei Makino Haruhiko Ono Midori Shirasaki Mikio Tada Norio Fujita Hisashi Ban Junko Ikeda Yukihiro Kawamoto Tomohiro Goto Mika Kimura Hiroyuki Baba Atsuo Yasuma Tsuneo |
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Institution: | Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohomachi, Yodogawa-ku, Osaka 532-8686, Japan. |
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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-tetrahydropyrazolo1,5-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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