Local anesthetics (LAs), such as lidocaine and mexiletine, inhibit bronchoconstriction in asthmatics, but adverse effects limit their use for this specific clinical application. In this study, we describe the anti-spasmodic properties of the mexiletine analog 2-(2-aminopropoxy)-3,5-dimethyl, 4-Br-benzene (JME-173), which was synthesized and screened for inducing reduced activity on Na channels. The effectiveness of JME-173 was assessed using rat tracheal rings, a GH3 cell line and mouse cardiomyocytes to access changes in smooth muscle contraction, and Na, and Caionic currents, respectively. Bronchospasm and airway hyper-reactivity (AHR) were studied using whole-body barometric plethysmography in A/J mice. We observed that the potency of JME-173 was 653-fold lower than mexiletine in inhibiting Na currents, but 12-fold higher in inhibiting L-type Ca currents. JME-173 was also more potent than mexiletine in inhibiting tracheal contraction by carbachol, allergen, extracellular Ca, or sodium orthovanadate provocations. The effect of JME-173 on carbachol-induced tracheal contraction remained unaltered under conditions of de-epithelized rings, β-receptor blockade or adenylate cyclase inhibition. When orally administered, JME-173 and theophylline inhibited methacholine-induced bronchospasm at time points of 1 and 3 h post-treatment, while only JME-173 remained active for at least 6 h. In addition, JME-173 also inhibited AHR in a mouse model of lipopolysaccharide (LPS)-induced lung inflammation. Thus, the mexiletine analog JME-173 shows highly attenuated activity on Na channels and optimized anti-spasmodic properties, in a mechanism that is at least in part mediated by regulation of Ca inflow toward the cytosol. Thus, JME-173 is a promising alternative for the treatment of clinical conditions marked by life-threatening bronchoconstriction.