Laboratorios Salvat SA

Background and purpose:  Highly selective M3 muscarinic receptor antagonists may represent a better treatment for overactive bladder syndrome, diminishing side effects. Cardiac side effects of non‐selective antimuscarinics have been associated with activity at M2 receptors as these receptors are mainly responsible for muscarinic receptor‐dependent bradycardia. We have investigated a novel antimuscarinic, SVT‐40776, highly selective for M3 over M2 receptors (Ki = 0.19 nmol·L−1 for M3 receptor affinity). This study reports the functional activity of SVT‐40776 in the bladder, relative to its activity in atria.Experimental approach: In vitro and ex vivo (oral dosing) inhibition of mouse detrusor and atrial contractile responses to carbachol were used to study the functional activity of SVT‐40776. The in vivo efficacy of SVT‐40776 was characterized by suppression of isovolumetric spontaneous bladder contractions in anaesthetized guinea pigs after intravenous administration.Key results:  SVT‐40776 was the most potent in inhibiting carbachol‐induced bladder contractions of the anti‐cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT‐40776 exhibited the highest urinary versus cardiac selectivity (199‐fold). In the guinea pig in vivo model, SVT‐40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 µg·kg−1 i.v), without affecting arterial blood pressure.Conclusions and implications:  SVT‐40776 is a potent inhibitor of M3 receptor‐related detrusor contractile activity. The absence of effects on isolated atria preparations represents an interesting characteristic and suggests that SVT‐40776 may lack unwanted cardiac effects; a feature especially relevant in a compound intended to treat mainly elderly patients.British Journal of Pharmacology (2009) doi:10.1111/j.1476‐5381.2008.00082.x

Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.

The antifungal activity of eberconazole, a new imidazole derivative, against 124 clinical isolates of Candida comprising eight different species and to 34 isolates of Cryptococcus neoformans was compared to those of clotrimazole and ketoconazole. MICs of eberconazole, determined by the National Committee for Clinical Laboratory Standards standardized microbroth method, were equal to or lower than those of other azoles, especially for Candida krusei and Candida glabrata , which are usually resistant to triazoles.