The discovery of a competitive phosphodiesterase (PDE) inhibitor is proposed which is specific for the low Km calmodulin (CaM) sensitive form of the PDE I isozyme (CaM-PDE). Inhibition of CaM-PDE will result in increases of intracellular cyclic nucleotides, most importantly cGMP. It is hypothesized that inhibition of this isozyme will result in vascular relaxation without effects on inotropy and thus provide a new means of treatment for cardiovascular disease. Chemical modifications and structure-activity studies will be pursued with the aim of establishing functional requirements for isozyme selectivity and increases in potency. In Phase I of this proposal, 6 to 10 novel and potentially patentable analogs will by synthesized and tested for PDE inhibition against cGMP-PDE I, CaM-PDE I and cAMP-PDE III isolated from bovine aorta. Compounds showing an order of magnitude selectivity for CaM-PDE vs. cGMP-PDE will be subsequently tested in an intact tissue assay for vasorelaxant properties. This test and additional in vivo assays, coupled with further structure- activity studies, would be undertaken in Phase II.
