title: Structure-activity relationship studies and discovery of a potent transient receptor potential vanilloid (TRPV1) antagonist 4-[3-chloro-5-[(1S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxamide (V116517) as a clinical candidate for pain management.
abstract: A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.
authors: Discovery Research, Purdue Pharma LP , 6 Cedar Brook Drive, Cranbury, New Jersey 08512, United States.
authors: Laykea
authors: L
authors: Tafesse
authors: Toshiyuki
authors: T
authors: Kanemasa
authors: Noriyuki
authors: N
authors: Kurose
authors: Jianming
authors: J
authors: Yu
authors: Toshiyuki
authors: T
authors: Asaki
authors: Gang
authors: G
authors: Wu
authors: Yuka
authors: Y
authors: Iwamoto
authors: Yoshitaka
authors: Y
authors: Yamaguchi
authors: Chiyou
authors: C
authors: Ni
authors: John
authors: J
authors: Engel
authors: Naoki
authors: N
authors: Tsuno
authors: Aniket
authors: A
authors: Patel
authors: Xiaoming
authors: X
authors: Zhou
authors: Takuya
authors: T
authors: Shintani
authors: Kevin
authors: K
authors: Brown
authors: Tsuyoshi
authors: T
authors: Hasegawa
authors: Manjunath
authors: M
authors: Shet
authors: Yasuyoshi
authors: Y
authors: Iso
authors: Akira
authors: A
authors: Kato
authors: Donald J
authors: DJ
authors: Kyle
mesh_terms: D000631:Aminopyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000700:Analgesics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003412:Cricetulus; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: C000595012:4-(3-chloro-5-(1,2-dihydroxyethyl)-2-pyridyl)-N-(5-(trifluoromethyl)-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxamide; D000631:Aminopyridines; D000700:Analgesics; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D005620:Freund's Adjuvant; D002211:Capsaicin; D002118:Calcium