title: 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.
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.
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan. Electronic address: naoki.tsuno@shionogi.co.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsuno
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yukimasa
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshida
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakai
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Fujiu
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takaya
authors.affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Nozu
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Shionogi Techno Advance Research Co., Ltd, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Funaki
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Ito
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Nagamatsu
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Asaki
authors.affiliation: Shionogi Techno Advance Research Co., Ltd, Japan.
authors.forename: Narumi
authors.initials: N
authors.lastname: Horita
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Mikie
authors.initials: M
authors.lastname: Hinata
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Soga
authors.affiliation: Pharmaceutical Research Division, Shionogi & Co., Ltd, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Imai
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Morioka
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kanemasa
authors.affiliation: Pharmaceutical Research Division, Shionogi & Co., Ltd, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd, Japan.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Iso
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006224:Cricetinae; D055808:Drug Discovery; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D013844:Thiazoles
keywords: Bi-cyclic piperazine; Ion channel; Pain; TRPV4 antagonist; Thiazole; Transient Receptor Potential Vanilloid 4; Trifluoromethyl pyrimidine; Vanilloid receptor