Identification of Benzoxazin-3-one Derivatives as Novel, Potent, and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists

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• 作者：Tomoaki Hasui ; Nobuyuki Matsunaga ; Taiichi Ora ; Norio Ohyabu ; Nobuhiro Nishigaki ; Yoshimi Imura ; Yumiko Igata ; Hideki Matsui ; Takashi Motoyaji ; Toshimasa Tanaka ; Noriyuki Habuka ; Satoshi Sogabe ; Midori Ono ; Christopher S. Siedem ; Tony P. Tang ; Cassandra Gauthier ; Lisa A. De Meese ; Steven A. Boyd ; Shoji Fukumoto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8616-8631
• 全文大小：562K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate鈥搒alt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.