title: Discovery of novel and potent orally active calcium-sensing receptor antagonists that stimulate pulselike parathyroid hormone secretion: synthesis and structure-activity relationships of tetrahydropyrazolopyrimidine derivatives.
abstract: As part of our research for novel calcium-sensing receptor (CaSR) antagonists that can function as oral bone anabolic agents, we recently reported the discovery of a tetrahydropyrazolopyrimidine derivative featuring adamantyl group 1b with potent CaSR antagonistic activity. To explore the potential of this calcilytic congener, we introduced the gem-dialkyl benzyl group at the 3-position of the tetrahydropyrazolopyrimidine ring, forming a bioisostere of the adamantyl group by mimicking the adamantyl group's lipophilicity and bulkiness. Optimization directed toward the improvement of solubility and metabolic stability led to the discovery of compound 9e, which stimulated transient PTH secretion when orally administered to normal rats. Further, compound 9e proved to be fully effective in an osteopenic ovariectomized rat model.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi-2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Yoshida_Masato@takeda.co.jp
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Mori
authors.forename: Etsuo
authors.initials: E
authors.lastname: Kotani
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Makino
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; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000503:physiopathology; D016466:CHO Cells; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D015394:Molecular Structure; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D050071:Bone Density Conservation Agents; C558527:N-(1-ethyl-1-(4-methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo(1,5-a)pyrimidine-3-carboxamide; D010281:Parathyroid Hormone; D011720:Pyrazoles; D011743:Pyrimidines; D044169:Receptors, Calcium-Sensing; D015675:Osteocalcin