In Phase l a novel class of xanthine-type compounds was identified that exert a selective inhibitory effect on the calmodulin-insensitive, cyclic GMP-specific subclass of phosphodiesterase (CAM-Ins/cGMP PDE). The best of these compounds (Compound 9) possesses an inhibitory profile comparable to that observed with the best characterized reference inhibitor of CAM- lns/cGMP PDE, M & B 22,948 (zaprinast). Recent reports indicate that agents like zaprinast may have considerable utility for treating cardiovascular disease, particularly hypertension and heart failure. These reports indicate that zaprinast i) exerts a direct vascular relaxation action, ii) selectively potentiates the vascular relaxant action of atrial natriuretic peptide (ANP). iii) lowers blood pressure without increasing heart rate, and iv) potentiates the diuretic and natriuretic action of ANP. The goal of the Phase Il portion of this SBIR Project Grant will be to use the structure-activity results obtained in the identification of Compound 9 for synthesizing compounds with even greater selectivity and potency. In addition, other more novel chemical approaches will be employed to capitalize on the discovery of Compound 9. All compounds with an acceptable degree of selectivity and potency for inhibition of the CAM- lns/cGMP PDE will then be examined in various in vitro and in vivo efficacy models aimed at assessing their potential utility for treating cardiovascular disease. Specifically, Compound 9 and other novel compounds will be evaluated for their ability to i) directly relax isolated vascular smooth muscle, ii) reduce total peripheral resistance without increasing heart rate, and iii) potentiate the in vitro and in vivo actions of ANP.
