title: Discovery of novel 5,5-diarylpentadienamides as orally available transient receptor potential vanilloid 1 (TRPV1) antagonists.
abstract: We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.
authors.affiliation: Fuji Research Park, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Suntou-gun, Shizuoka 411-8731, Japan. osamu.saku@kyowa-kirin.co.jp
authors.forename: Osamu
authors.initials: O
authors.lastname: Saku
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishida
authors.forename: Eri
authors.initials: E
authors.lastname: Atsumi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kodaira
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Kato
authors.forename: Shiro
authors.initials: S
authors.lastname: Shirakura
authors.forename: Yoshisuke
authors.initials: Y
authors.lastname: Nakasato
mesh_terms: D000466:Alkadienes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004285:Dogs; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D057809:HEK293 Cells; D000882:Haplorhini; D006801:Humans; D006930:Hyperalgesia / Q000517:prevention & control; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009437:Neuralgia / Q000517:prevention & control; D015363:Quinolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000466:Alkadienes; D000577:Amides; D000700:Analgesics; D019309:Epstein-Barr Virus Nuclear Antigens; D015363:Quinolones; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; C417029:EBV-encoded nuclear antigen 1; D002211:Capsaicin; D002118:Calcium