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Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2006 Jul 15; Vol. 14 (14), pp. 4740-9. Date of Electronic Publication: 2006 Apr 18. - Publication Year :
- 2006
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 14
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16621571
- Full Text :
- https://doi.org/10.1016/j.bmc.2006.03.027