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,Bioorganic & Medicinal Chemistry Letters

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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
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2016-10-17 14:43:08
Naoki Tsuno, Akira Yukimasa, Osamu Yoshida, Yusuke Ichihashi, Takatsugu Inoue, Tatsuhiko Ueno, Hiroki Yamaguchi, Hidetoshi Matsuda, Satoko Funaki, Natsue Yamanada, Miki Tanimura, Daiki Nagamatsu, Yoko Nishimura, Tetsuji Ito, Masahiko Soga, Narumi Horita, Miyuki Yamamoto, Mikie Hinata, Masayuki Imai, Yasuhide Morioka, Toshiyuki Kanemasa, Gaku Sakaguchi, Yasuyoshi Iso

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).

中文翻译：

新型2'，4'-二甲基-[4,5'-bithiazol] -2-基氨基衍生物作为口服生物可利用的TRPV4拮抗剂治疗疼痛的发现：第1部分

通过高通量筛选TRPV4受体，发现了一系列新的2'，4'-二甲基-[4,5'-bithiazol] -2-基氨基衍生物，这些化合物在这些化合物上显示出对4α-佛波醇12的竞争性拮抗剂潜力。，13-十二烷酸酯（4αPDD）作为选择性TRPV4激动剂，对TRPV1，N型和L型钙离子通道显示出优异的选择性，但ADME谱较差。在我们的SAR策略中，我们发现在右侧部分还具有独特的3-oxa-9-azabicyclo [3.3.1] nonan-7-one的先导分子1显示出强力的TRPV4拮抗剂活性，在pH 6.8时良好的溶解性，良好的对人的微粒体稳定性和更好的ADME谱，包括口服生物利用度。此外，化合物1在豚鼠的弗氏完全佐剂（FCA）诱发的机械痛觉过敏模型中具有镇痛作用。在这封信中，

更新日期：2016-10-18

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