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 |
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Authors: | Gomtsyan Arthur Bayburt Erol K Schmidt Robert G Zheng Guo Zhu Perner Richard J Didomenico Stanley Koenig John R Turner Sean Jinkerson Tammie Drizin Irene Hannick Steven M Macri Bryan S McDonald Heath A Honore Prisca Wismer Carol T Marsh Kennan C Wetter Jill Stewart Kent D Oie Tetsuro Jarvis Michael F Surowy Carol S Faltynek Connie R Lee Chih-Hung |
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Affiliation: | Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. arthur.r.gomtsyan@abbott.com |
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Abstract: | 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. |
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