The Pharmacological Research Of VGD53, A Novel Phosphodiesterase Inhibitor

Sildenafil, a typical PDEI5, is recognized as fast selective and potent drug of treating male erectile dysfunction (MED). VGD1-60, a series of derivatives of sildenafil were synthesized by the researchers of Chemistry Synthesis Department of ShenYang Pharmaceutical University. The present study was firstly designed to screen and gain the pharmacological roles in relaxation of isolated guinea-pigs tracheal smooth muscle and isolated rabbits arotic smooth muscle, and isolated guinea-pigs heart. The result showed that, at 1.0×10-5M concentration, a number of compounds among VGD1-60 showed activities of relaxing tracheal and arotic smooth muscle respectively, and that VGD55 and VGD10 increase coronary blood flow at dose of 1.2×10-5 mol. The pharmacological effects of VGD9 and VGD21 on isolated guinea-pig heart contractivity like those of Milironine which is a selective PDE3 inhibitors.It was demonstrated that VGD53 (1.2×10-6mol) not only directively increased the amount of perfusate escaping from the lung surface (APEL) out of mice and guinea-pigs , but increase APEL challenged by ovalbumin out of allergic guinea- pigs, that VGD53 (1.0 ×10-5M) relaxed not only isolated guinea-pigs tracheal and lung strips precontracted histamine (10-6mg/ml), but isolated allergic guinea- pigs tracheal and lung strips challenged by ovalbumin or precontracted histamine. Pretreatment (] h) with VGD53 (1.2 × 10-5mol/kg,3.37mg/kg, i.p.) prolonged siginicantly induced asthmatic potential period in normal and allergic guinea-pig models. Moreover, VGD53 (1.4× 10-5mol/kg, 4.28 mg/kg,i.p.) reduced airway hyperresponsiveness (AHR) and the acute bronchoconstriction, expanded bronchi diameter, inhibited infiltraion of inflammatory cell in lung in allergic rat models. In normal rats, it markedly prevented mast cell degranulation of skull membrane at the same doses.In addition, VGD53 (7.2×10"6 mol/kg, 2.2 mg/kg,i.v.) decreased lung overflow in anaesthetized rabbits induced by Ach (10-3mg/ml, i.v.), inhibited dose-dependently (from 10-8M to 10-5M) PDEs of rabbit platelet.From these result, we had made a conclusion that VGD53 have potent pharmacological activities for the treatment of asthma, and do further studies on development of novel phosphodiesterase inhibitors.