Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists |
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Authors: | Drizin Irene Gomtsyan Arthur Bayburt Erol K Schmidt Robert G Zheng Guo Zhu Perner Richard J DiDomenico Stanley Koenig John R Turner Sean C Jinkerson Tammie K Brown Brian S Keddy Ryan G McDonald Heath A Honore Prisca Wismer Carol T Marsh Kennan C Wetter Jill M Polakowski James S Segreti Jason A Jarvis Michael F Faltynek Connie R Lee Chih-Hung |
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Institution: | Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Il 60064, USA. irene.drizin@abbott.com |
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Abstract: | Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose. |
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