In Vitro Structure−Activity Relationship and In Vivo Characterization of 1-(Aryl)-3-(4-(amino)benzyl)urea Transient Receptor Potential Vanilloid 1 Antagonists

The synthesis and structure−activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquino...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-07, Vol.50 (15), p.3651-3660
Main Authors: Perner, Richard J, DiDomenico, Stanley, Koenig, John R, Gomtsyan, Arthur, Bayburt, Erol K, Schmidt, Robert G, Drizin, Irene, Zheng, Guo Zhu, Turner, Sean C, Jinkerson, Tammie, Brown, Brian S, Keddy, Ryan G, Lukin, Kurill, McDonald, Heath A, Honore, Prisca, Mikusa, Joe, Marsh, Kennan C, Wetter, Jill M, St. George, Karen, Jarvis, Michael F, Faltynek, Connie R, Lee, Chih-Hung
Format: Article
Language:English
Subjects:
Administration, Oral
Analgesics - chemical synthesis
Analgesics - pharmacokinetics
Analgesics - pharmacology
Animals
Biological and medical sciences
Biological Availability
Dogs
Drug Stability
Humans
In Vitro Techniques
Indazoles - chemical synthesis
Indazoles - pharmacokinetics
Indazoles - pharmacology
Isoquinolines - chemical synthesis
Isoquinolines - pharmacokinetics
Isoquinolines - pharmacology
Medical sciences
Microsomes, Liver - metabolism
Miscellaneous
Pharmacology. Drug treatments
Phenylurea Compounds - chemical synthesis
Phenylurea Compounds - pharmacokinetics
Phenylurea Compounds - pharmacology
Rats
Structure-Activity Relationship
TRPV Cation Channels - antagonists & inhibitors
Urea - analogs & derivatives
Urea - chemical synthesis
Urea - pharmacokinetics
Urea - pharmacology
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Summary:The synthesis and structure−activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070276i