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
Affiliations
  • 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.