title: Pharmacological evaluation of novel (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives as TRPV4 antagonists for the treatment of pain.
abstract: A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig and rat. Modification of right part based on the compound 16d which was disclosed in our previous communication led to the identification of compound 26i as a flagship compound. In this paper, we described the details about design, synthesis and structure-activity relationship (SAR) analysis at right and left part of these derivatives (Fig. 1).
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan. Electronic address: naoki.tsuno@shionogi.co.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsuno
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yukimasa
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshida
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nakai
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Fujiu
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takaya
authors.affiliation: Medicinal Chemistry Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Nozu
authors.affiliation: Medicinal Chemistry Research Laboratory, 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: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Natsue
authors.initials: N
authors.lastname: Yamanada
authors.affiliation: Drug Discovery & Disease Research Laboratory, 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: Drug Discovery & Disease Research Laboratory, 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: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Mikie
authors.initials: M
authors.lastname: Hinata
authors.affiliation: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Soga
authors.affiliation: Global Innovation Office, Shionogi & Co., Ltd, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Imai
authors.affiliation: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Morioka
authors.affiliation: Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kanemasa
authors.affiliation: Global Innovation Office, Shionogi & Co., Ltd, Japan.
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.affiliation: IMP Manufacturing Center, CMC R&D Division, Shionogi & Co., Ltd, Japan.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Iso
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008861:Microsomes / Q000187:drug effects; D059408:Pain Management / Q000379:methods*; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000622717:(6-((2',4'-dimethyl-(4,5'-bithiazol)-2-yl)amino)pyridin-3-yl)(7-(5-(trifluoromethyl)pyrimidin-2-yl)-3-oxa-7,9-diazabicyclo(3.3.1)nonan-9-yl)methanone; D000700:Analgesics; D053961:Azabicyclo Compounds; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D013844:Thiazoles
keywords: Ion channel; Pain; TRPV4 antagonist; Transient receptor potential vanilloid 4; Vanilloid receptor