Cardiotonic agents. 8. Selective inhibitors of adenosine 3',5'-cyclic phosphate phosphodiesterase III. Elaboration of a five-point model for positive inotropic activity

Inhibitors of adenosine 3',5'-cyclic phosphate phosphodiesterase III (cAMP PDE III) were studied by using solid-state, solution, and theoretical methods in order to refine a five-point model for positive inotropic activity. Cyclic AMP PDE III inhibitors bear a striking resemblance to cAMP itself. This investigation supports the importance of an overall planar topography for selective and potent cAMP PDE III inhibition. (Possible reasons for the potency of certain nonplanar compounds are discussed.) Cardiotonics like imazodan (1; CI-914) and 2 (CI-930) can readily achieve essentially planar geometries, as shown with X-ray crystallographic, IR, UV, NMR, and theoretical data. Small alkyl substituents that occupy space corresponding to certain portions of the cAMP sugar region increase potency (see, e.g., 2, 4). Selective inhibition of cAMP PDE III can be achieved by mimicking the attractive electrostatic potential associated with the phosphate group (e.g., with an amide) and by providing an additional attractive potential spatially opposite to the previous one, in the vicinity of the adenine N1 and extending to N3 (e.g., with an imidazole), together with a partial dipole moment comparable to the adenine dipole moment. This extends and better defines our five-point model in terms of cAMP, a natural substrate for PDE.