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

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 7; pp. 2177 - 2190
• Main Authors: Tsuno, Naoki, Yukimasa, Akira, Yoshida, Osamu, Suzuki, Shinji, Nakai, Hiromi, Ogawa, Tomoyuki, Fujiu, Motohiro, Takaya, Kenji, Nozu, Azusa, Yamaguchi, Hiroki, Matsuda, Hidetoshi, Funaki, Satoko, Yamanada, Natsue, Tanimura, Miki, Nagamatsu, Daiki, Asaki, Toshiyuki, Horita, Narumi, Yamamoto, Miyuki, Hinata, Mikie, Soga, Masahiko, Imai, Masayuki, Morioka, Yasuhide, Kanemasa, Toshiyuki, Sakaguchi, Gaku, Iso, Yasuyoshi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2017; Elsevier
• Subjects: Analgesics - chemistry; Analgesics - pharmacology; Animals; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - pharmacology; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Guinea Pigs; Humans; Ion channel; Life Sciences & Biomedicine; Microsomes - drug effects; Pain; Pain Management - methods; Pharmacology & Pharmacy; Physical Sciences; Proton Magnetic Resonance Spectroscopy; Rats; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - pharmacology; Transient receptor potential vanilloid 4; TRPV Cation Channels - antagonists & inhibitors; TRPV4 antagonist; Vanilloid receptor; TRPV4 antagonist; Pain; Vanilloid receptor; Transient receptor potential vanilloid 4; Ion channel; ACTIVATION; RAT; TYROSINE KINASE; INTEGRIN; CATION CHANNEL; NEUROPATHIC PAIN; MECHANICAL HYPERALGESIA; RECEPTOR POTENTIAL VANILLOID-4; TRANSIENT
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.02.047

[Display omitted] 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).