Abstract 3465: A Direct Inhibitor of Smooth Muscle Myosin as a Novel Therapeutic Approach for the Treatment of Pulmonary Artery Hypertension
Smooth muscle myosin is a mechanochemical enzyme that hydrolyzes ATP to generate mechanical force; ultimately all signaling pathways that modulate smooth muscle tone converge on the regulation of this motor protein. Existing therapies for pulmonary artery hypertension (PAH) such as endothelin antagonists, prostacyclin analogs and phosphodiesterase inhibitors indirectly modulate actin-myosin cross bridging to elicit smooth muscle relaxation. Given its central role in generating smooth muscle contractility, direct inhibition of smooth muscle myosin (SMM) should provide a novel and effective means to reduce pulmonary arterial pressure and pulmonary vascular resistance. Using high throughput screening, we identified and subsequently optimized a class of selective inhibitors of SMM. CK-2018571, a compound from this class, inhibited the SMM ATPase activity with an IC50 of 30 nM and inhibited the calcium-induced contraction of skinned rat tail artery by greater than 90% at 1 μM. CK-2018571 also induced a concentration-dependent relaxation of pre-constricted pulmonary artery from normal rats and monocrotaline-induced PAH rats with an IC50 of 1 μM.
CK-2019165, a pro-drug of CK-2018571 designed to increase its solubility, administered by direct intra-tracheal nebulization induced a significant dose-dependent reduction (P<0.01) in elevated right ventricular systolic pressure in U-46619 (thromboxane analog)-induced and monocrotaline-induced PAH rats. Together these data suggest that SMM inhibition may provide a viable and novel therapeutic approach for the treatment of PAH.