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

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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 ; Shinji Suzuki^a ; Hiromi Nakai^a ; Tomoyuki Ogawa^a ; Motohiro Fujiu^a ; Kenji Takaya^a ; Azusa Nozu^b ; Hiroki Yamaguchi^a ; Hidetoshi Matsuda^c ; Satoko Funaki^d ; Yoko Nishimura^d ; Tetsuji Ito^d ; Daiki Nagamatsu^d ; Toshiyuki Asaki^a ; Narumi Horita^c ; Miyuki Yamamoto^a ; Mikie Hinata^a ; Masahiko Soga^a ; Masayuki Imai^e ; Yasuhide Morioka^a ; Toshiyuki Kanemasa^a ; Gaku Sakaguchi^e ; Yasuyoshi Iso^a
• 关键词：Transient Receptor Potential Vanilloid 4 ; TRPV4 antagonist ; Ion channel ; Vanilloid receptor ; Thiazole ; Trifluoromethyl pyrimidine ; Bi-cyclic piperazine ; 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：4936-4941
• 全文大小：2428 K

文摘

A series of 2′,4′-dimethyl-[4,5′-bithiazol]-2-yl amino derivatives have been identified as selective TRPV4 antagonists that display inhibition potencies against 4α-phorbol 12,13-didecanoate (4αPDD), well known as a TRPV4 selective agonist and/or a hypotonicity. In particular, 9-(6-((2′,4′-dimethyl-[4,5′-bithiazol]-2-yl)amino)nicotinoyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one showed an analgesic effect in Freund’s Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig (reported in Part 1). However, there are some concerns such as species differences and the need for higher plasma exposure to achieve target efficacy for evaluation by an in vivo pain model. In this Letter, we report the resolution of some of the problems by further optimizing the chemical scaffold.