DISCOVERY OF NOVEL SPIROCYCLIC COMPOUNDS FOR THE TREATMENT OF MYOCARDIAL REPERFUSION INJURY

Acute myocardial infarction (MI) is one of the leading causes of death and disability worldwide and reperfusion injury (RI) is known to contribute for up to the 50% of the final infarct size. Rising data indicate that the onset of RI involves several molecular and cellular factors that culminate in the final opening of a large pore in the mitochondrial membrane, namely the mitochondrial permeability transition pore (mPTP).[1] mPTP is recognized as the key actor in the final step of RI and the main responsible for cardiomyocyte death, which makes it a major therapeutic target for cardioprotection. The incomplete knowledge of the bio architecture of mPTP is the main obstacle in drug discovery programs, however recent findings suggest that mPTP would reside in the c‐ring of F1FO-ATP synthase.[2] Our research group supported this evidence reporting the discovery of the first smallmolecule inhibitors of mPTP that target the c subunit of F1/FO-ATP synthase.[3] PP11, the parent compound of the series, was designed from the structure of Oligomycin A, a known c ring ligand (Fig. 1). The following SAR optimization led to IB13 which showed beneficial effects in an ex vivo model of MI.[3] Based on these preliminary results we focused on the design and synthesis of isatin-based spirocycles with the general structure MF, in order to identify novel clinically useful mPTP inhibitors (unpublished). The synthesized molecules were tested in vitro, and all these novel spiro-derivatives demonstrated to inhibit mPTP opening. Specifically, compound MF16 (Fig. 1) is the most promising compound of the series, with an 83% inhibition at 1µM concentration.