The central role of NHE1 in myocardial pH regulation has prompted considerable interest in the development of NHE1 inhibitors for the treatment of ischemia-reperfusion injury. Recent emergence of data to support a role for NHE1 inhibition in heart failure led to our interest in pursuing an NHE1 inhibitor as a treatment for chronic heart failure. This report outlines our efforts to identify a NHE1 inhibitor suitable for once daily oral administration with minimal potential for drug-drug interactions. Our discovery efforts initiated from sabiporide, beginning with a change to the basic scaffold structure to move outside of the previously explored chemical space. Subsequent optimization focused on improvements in potency, reduction of DDI potential as measured by CYP inhibition, and improvements in pharmacokinetics. These efforts resulted in the successful identification of a compound that displays high potency, very low CYP inhibition, and improved pharmacokinetics. The pharmacological evaluation of this compound in an isolated heart model of ischemia reperfusion injury (Langendorff isolated heart preparation) revealed the ability to potently prevent ischemic damage.

Identification of a potent NHE1 inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat

241st National Meeting (2011)

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