Discovery of Novel and Potent Orally Active Calcium-Sensing Receptor Antagonists that Stimulate Pulselike Parathyroid Hormone Secretion: Synthesis and Structure鈭扐ctivity Relationships of Tetrahydropyr

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• 作者：Masato Yoshida ; Akira Mori ; Etsuo Kotani ; Masahiro Oka ; Haruhiko Makino ; Hisashi Fujita ; Junko Ban ; Yukihiro Ikeda ; Tomohiro Kawamoto ; Mika Goto ; Hiroyuki Kimura ; Atsuo Baba ; Tsuneo Yasuma
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1430-1440
• 全文大小：1032K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

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鈥檚 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.