title: 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.
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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 2-17-85, Jusohomachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Mori
authors.forename: Shinji
authors.initials: S
authors.lastname: Morimoto
authors.forename: Etsuo
authors.initials: E
authors.lastname: Kotani
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.forename: Kohei
authors.initials: K
authors.lastname: Notoya
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Makino
authors.forename: Midori
authors.initials: M
authors.lastname: Ono
authors.forename: Mikio
authors.initials: M
authors.lastname: Shirasaki
authors.forename: Norio
authors.initials: N
authors.lastname: Tada
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujita
authors.forename: Junko
authors.initials: J
authors.lastname: Ban
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Mika
authors.initials: M
authors.lastname: Goto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Atsuo
authors.initials: A
authors.lastname: Baba
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yasuma
mesh_terms: D000284:Administration, Oral; D045930:Anabolic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008252:Macaca fascicularis; D008968:Molecular Conformation; D010024:Osteoporosis / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D045930:Anabolic Agents; C559074:N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo(1,5-a)pyrimidine-3-carboxamide; D010281:Parathyroid Hormone; D011720:Pyrazoles; D011743:Pyrimidines; D044169:Receptors, Calcium-Sensing