1. Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists.
- Author
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Drizin I, Gomtsyan A, Bayburt EK, Schmidt RG, Zheng GZ, Perner RJ, DiDomenico S, Koenig JR, Turner SC, Jinkerson TK, Brown BS, Keddy RG, McDonald HA, Honore P, Wismer CT, Marsh KC, Wetter JM, Polakowski JS, Segreti JA, Jarvis MF, Faltynek CR, and Lee CH
- Subjects
- Animals, In Vitro Techniques, Kinetics, Male, Mice, Motor Activity drug effects, Pain Measurement, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, TRPV Cation Channels metabolism, Urea chemical synthesis, Urea chemistry, Urea pharmacology, TRPV Cation Channels antagonists & inhibitors, Urea analogs & derivatives
- 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.
- Published
- 2006
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