Design, Synthesis, and Structure-Activity Relationships of the First Highly Potent, Selective, and Bio Available Adenosine 5′-Monophosphate Deaminase Inhibitors

In the preceding article1 we described our strategy for the discovery of a series of cell penetrable AMP deaminase (AMPDA) inhibitors for postulated use in the treatment of ischemia, especially of the myocardium, and any other conditions expected to benefit from site- and event-specific enhancement of extracellular adenosine. The initial set of compounds, prepared as a preliminary test of our design concept and represented by 1, exhibited only modest potency and selectivity. We thus viewed 1 as a lead structure which would require further optimization to maximize the potency, and accordingly initiated a study to probe the structure-activity profile of this new series. Herein, we report our SAR study which led to the discovery of a series of highly potent and highly selective AMPDA inhibitors.