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 1.
abstract: 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).
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: Yusuke
authors.initials: Y
authors.lastname: Ichihashi
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ueno
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: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan.
authors.forename: Natsue
authors.initials: N
authors.lastname: Yamanada
authors.affiliation: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tanimura
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd., Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Nagamatsu
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: Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Soga
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: 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; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D006801:Humans; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors
chemical_list: D000700:Analgesics; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human
keywords: Bi-cyclic; Ion channel; Pain; TRPV4 antagonist; Thiazole; Transient Receptor Potential Vanilloid 4; Vanilloid receptor