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Despite the thousands of studies on drug therapy designed to reduce myocardial infarct size (IS), almost none have been successfully translated to the clinics. A major reason for failure is that many of these drugs are only effective when administered before coronary artery reperfusion (CAR), which limits their utility in the clinical setting, where CAR must be instituted immediately in patients after the myocardial infarction (MI) diagnosis has been made, not leaving time for drug therapy. It is also important that the drug does not increase myocardial oxygen consumption. In our prior work on the adenylyl cyclase type 5 (AC5) knock out (KO) mouse model, we found that it enhanced longevity, protected against diabetes and obesity, improved exercise performance and reduced IS after coronary artery occlusion (CAO) and CAR. Based on these studies, and since it is difficult to delete genes in humans, we developed a novel pharmacological candidate to inhibit AC5, named C90. C90 reduced AC activity and cAMP in response to forskolin more than vehicle, (12.9±1.9 vs. 14.2 ± 3.1 pmol/mg/min). However, in AC5 KO C90 no longer reduced cAMP in response to forskolin, indicating its selectivity for AC5 inhibition. The goal of this investigation was to examine the new AC5 inhibitor, C90, and compare its efficacy in reducing IS when the drug was delivered after CAR with that of adenosine, the gold standard for ischemic cardioprotection. Wild type (WT) mice were subjected to 30 min CAO followed by 24 hours CAR. C90 or vehicle was then administered at 5 min after CAR by intravenous (IV) administration at doses of 0.01, 0.03, 0.06, 0.6, and 1.2 mg/kg. The area at risk was similar in all groups, determined by triphenyltetrazolium chloride (TTC) staining. IS was reduced in a dose‐response manner by C90. IS was reduced by 32% at a dose of 0.06 mg/kg of C90, whereas the same dose of adenosine reduced IS similarly when administered before CAR but failed to reduce IS when administered after CAR. C90 further reduced IS by 64% at a dose of 0.6 mg/kg and by 71% at a dose of 1.2 mg/kg. When C90 was delivered at 10 min after CAR, it still IS by 50% and 53% at doses of 0.6 mg/kg and 1.2 mg/kg, respectively. In addition, LV ejection fraction (LV EF) was also examined at 4 weeks after myocardial infarction in mice, and was preserved in the C90 group (LVEF = 65±1.6%) vs. the vehicle group (LVEF = 52±2.9%). C90 also reduced IS by 49% in the Watanabe rabbit, model of atherosclerosis. Thus, C90, an inhibitor of AC5, is a novel target for clinical development, since it reduces myocardial IS when delivered after reperfusion, a key feature for patients coming to the emergency room, where reperfusion must be carried out before additional therapy. An additional advantageous feature of C90 and inhibition of AC5, is that it reduces beta‐adrenergic receptor signaling and myocardial oxygen consumption, which are important for patients with heart disease. Support or Funding Information NIH R21AG053514; NIH R44 HL142390; NIH R44HL112512 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .