Discovery of novel 2′,4′-dimethyl-[4,5′-bithiazol]-2-yl amino derivatives as orally bioavailable TRPV4 antagonists for the treatment of pain: Part 1

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• 作者：Naoki Tsuno^a ; ^{naoki.tsuno@shionogi.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Akira Yukimasa^a ; Osamu Yoshida^a ; Yusuke Ichihashi^a ; Takatsugu Inoue^a ; Tatsuhiko Ueno^a ; Hiroki Yamaguchi^a ; Hidetoshi Matsuda^b ; Satoko Funaki^c ; Natsue Yamanada^a ; Miki Tanimura^a ; Daiki Nagamatsu^c ; Yoko Nishimura^c ; Tetsuji Ito^c ; Masahiko Soga^a ; Narumi Horita^b ; Miyuki Yamamoto^a ; Mikie Hinata^a ; Masayuki Imai^d ; Yasuhide Morioka^a ; Toshiyuki Kanemasa^a ; Gaku Sakaguchi^d ; Yasuyoshi Iso^a
• 关键词：Transient Receptor Potential Vanilloid 4 ; TRPV4 antagonist ; Ion channel ; Vanilloid receptor ; Thiazole ; Bi-cyclic ; Pain
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：26
• 期：20
• 页码：4930-4935
• 全文大小：2093 K

文摘

A novel series of 2′,4′-dimethyl-[4,5′-bithiazol]-2-yl amino derivatives were found by high throughput screening of the TRPV4 receptor, at which these compounds showed competitive antagonist potential against 4α-phorbol 12,13-didecanoate (4αPDD) as the selective TRPV4 agonist and showed excellent selectivity for TRPV1, N-type and L-type calcium ion channels, but poor ADME profile. In our SAR strategy, we found that the lead molecule 1 also having the unique 3-oxa-9-azabicyclo [3.3.1] nonan-7-one on the right part showed potent TRPV4 antagonist activity, good solubility at pH 6.8, good microsomal stability for human and better ADME profile including oral bioavailability. Moreover, compound 1 had an analgesic effect in Freund’s Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig. In this letter, we report a lead optimization process to identify the lead compound 1 (Fig. 1).