title: Tetrahydropyridine-4-carboxamides as novel, potent transient receptor potential vanilloid 1 (TRPV1) antagonists.
abstract: A series of 1,2,3,6-tetrahydropyridyl-4-carboxamides, exemplified by 6, have been synthesized and evaluated for in vitro TRPV1 antagonist activity, and in vivo analgesic activity in animal pain models. The tetrahydropyridine 6 is a novel TRPV1 receptor antagonist that potently inhibits receptor-mediated Ca2+ influx in vitro induced by several agonists, including capsaicin, N-arachidonoyldopamine (NADA), and low pH. This compound penetrates the CNS and shows potent anti-nociceptive effects in a broad range of animal pain models upon oral dosing due in part to its ability to antagonize both central and peripheral TRPV1 receptors. The SAR leading to the discovery of 6 is presented in this report.
authors: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Dept R4PM, AP10-207, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA. brian.s.brown@abbott.com
authors: Brian S
authors: BS
authors: Brown
authors: Ryan
authors: R
authors: Keddy
authors: Guo Zhu
authors: GZ
authors: Zheng
authors: Robert G
authors: RG
authors: Schmidt
authors: John R
authors: JR
authors: Koenig
authors: Heath A
authors: HA
authors: McDonald
authors: Bruce R
authors: BR
authors: Bianchi
authors: Prisca
authors: P
authors: Honore
authors: Michael F
authors: MF
authors: Jarvis
authors: Carol S
authors: CS
authors: Surowy
authors: James S
authors: JS
authors: Polakowski
authors: Kennan C
authors: KC
authors: Marsh
authors: Connie R
authors: CR
authors: Faltynek
authors: Chih-Hung
authors: CH
authors: Lee
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D011725:Pyridines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D011725:Pyridines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C474941:arachidonyl dopamine; D002211:Capsaicin; D002118:Calcium; D004298:Dopamine