A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy

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• 作者：Hirotaka Kashiwagi ; ^{kashiwagihrt@chugai-pharm.co.jp} ; Yoshiyuki Ono ; Masateru Ohta ; Susumu Itoh ; Fumihiko Ichikawa ; Suguru Harada ; Satoshi Takeda ; Nobuo Sekiguchi ; Masaki Ishigai ; Tadakatsu Takahashi
• 关键词：Vitamin D3 ; VDR agonist ; Nonsecosteroid ; Osteoporosis ; CH5036249
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 April, 2013
• 年：2013
• 卷：21
• 期：7
• 页码：1823-1833
• 全文大小：1262 K

文摘

In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)₂D₃ had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)₂D₃. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D₃ analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human.