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Novel Transient Receptor Potential Vanilloid 1 Receptor Antagonists for the Treatment of Pain: Structure−Activity Relationships for Ureas with Quinoline, Isoquinoline, Quinazoline, Phthalazine, Quinoxaline, and Cinnoline Moieties

2005; American Chemical Society; Volume: 48; Issue: 3 Linguagem: Inglês

10.1021/jm0492958

1520-4804

Arthur Gomtsyan, Erol K. Bayburt, Robert George Schmidt, Guo Zhu Zheng, Richard J. Perner, Stanley DiDomenico, John R. Koenig, Sean Turner, Tammie K. Jinkerson, Irene Drizin, Steven M. Hannick, Bryan S. Macri, Heath A. McDonald, Prisca Honoré, Carol T. Wismer, Kennan C. Marsh, Jill M. Wetter, Kent D. Stewart, Tetsuro Oie, Michael F. Jarvis, Carol S. Surowy, Connie R. Faltynek, Chih‐Hung Lee,

Ion channel regulation and function

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.