| Literature DB >> 27634196 |
Naoki Tsuno1, Akira Yukimasa2, Osamu Yoshida2, Shinji Suzuki2, Hiromi Nakai2, Tomoyuki Ogawa2, Motohiro Fujiu2, Kenji Takaya2, Azusa Nozu3, Hiroki Yamaguchi2, Hidetoshi Matsuda4, Satoko Funaki5, Yoko Nishimura5, Tetsuji Ito5, Daiki Nagamatsu5, Toshiyuki Asaki2, Narumi Horita4, Miyuki Yamamoto2, Mikie Hinata2, Masahiko Soga2, Masayuki Imai6, Yasuhide Morioka2, Toshiyuki Kanemasa2, Gaku Sakaguchi6, Yasuyoshi Iso2.
Abstract
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.Entities:
Keywords: Bi-cyclic piperazine; Ion channel; Pain; TRPV4 antagonist; Thiazole; Transient Receptor Potential Vanilloid 4; Trifluoromethyl pyrimidine; Vanilloid receptor
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Year: 2016 PMID： 27634196 DOI： 10.1016/j.bmcl.2016.09.014
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823