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

2007; American Chemical Society; Volume: 50; Issue: 15 Linguagem: Inglês

10.1021/jm070276i

1520-4804

Richard J. Perner, Stanley DiDomenico, John R. Koenig, Arthur Gomtsyan, Erol K. Bayburt, Robert George Schmidt, Irene Drizin, Guo Zhu Zheng, Sean Turner, Tammie K. Jinkerson, Brian S. Brown, Ryan G. Keddy, Kurill Lukin, Heath A. McDonald, Prisca Honoré, Joe Mikusa, Kennan C. Marsh, Jill M. Wetter, Karen St. George, Michael F. Jarvis, Connie R. Faltynek, Chih‐Hung Lee,

Ion channel regulation and function

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.