Discovery of 5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities

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• 作者：Nobuki Sakauchi ; Yasuhisa Kohara ; Ayumu Sato ; Tomohiko Suzaki ; Yumi Imai ; Yuichi Okabe ; Shigemitsu Imai ; Reiko Saikawa ; Hiroshi Nagabukuro ; Haruhiko Kuno ; Hisashi Fujita ; Izumi Kamo ; Masato Yoshida
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：2989-3002
• 全文大小：580K
• 年卷期：0
• ISSN：1520-4804

文摘

A novel structural class of iminopyridine derivative 1 was identified as a potent and selective human α_1D adrenoceptor (α_1D adrenergic receptor; α_1D-AR) antagonist against α_1A- and α_1B-AR through screening of an in-house compound library. From initial structure–activity relationship studies, we found lead compound 9m with hERG K⁺ channel liability. To develop analogues with reduced hERG K⁺ channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (R)-9s and 9u, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, 9u was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective α_1D-AR antagonists and evaluate their effects in vivo.