Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists

Bioorganic & Medicinal Chemistry
Irene DrizinChih-Hung Lee

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.

Citations

May 29, 2010·Organic Letters·Benjamin J StokesTom G Driver
Feb 4, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Andras GaramiAndrej A Romanovsky
Feb 6, 2008·Molecular and Cellular Neurosciences·Thomas ChristophJens Kurreck
Nov 14, 2008·Magnetic Resonance in Chemistry : MRC·M Angeles GarcíaJosé Elguero
Jun 27, 2019·Medicinal Chemistry·Nehaben A GujaratiVijaya L Korlipara
Oct 17, 2008·Journal of Combinatorial Chemistry·Damijana Urankar, Janez Kosmrlj

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