The a-adrenergic receptors belong to a class of G-protein-coupled receptors. They are further divided into several subtypes a1-(1A, 1B, 1D) and a2-(2A, 2B, 2C). Nasal congestion is a symptom induced by the swelling of venous sinusoids and mucosal engorgement. Nasal congestion is treated by constricting the nasal vasculature and decreasing the blood flow through the nasal mucosa. Standard oral decongestants pseudoephedrine (PSE) and phenylepherine (PE) are non-selective a-adrenergic receptor agonists, with side-effects such as hypertension, stroke and abuse potential. Selective activation of the a2C adrenergic receptors has been shown to constrict the venous nasal vasculature and produce decongesting activity in animal model, suggesting that peripheral-acting, selective a2C agonists have great therapeutic value for the treatment of decongestion with potentially improved side-effect profile over current marketed drugs. Herein, we disclose the synthesis and SAR study of two novel series of a2C agonists based on the chroman and tetrahydroquinoline core. The urea analog from chroman series exhibits in vivo efficacy at 1 mg/kg in our cat decongestion model.

Discovery and SAR studies of (imidazolylmethyl)chroman, a potent and selective α2C agonist, as a treatment of nasal congestion

244th National Meeting (2012)

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