SYNTHESIS AND ANALYSIS OF PYRENE-CONTAINING LISINOPRIL ANALOGS TO STUDY ACE INHIBITION

Abstract

Cardiovascular disease (CVD) is a leading cause of death worldwide. One of the major risk factors in developing CVD is hypertension, characterized by extended periods of increased blood pressure. Blood pressure is managed by the renin-angiotensin-aldosterone system (RAAS), of which angiotensin converting enzyme (ACE) is a key player. Lisinopril, one of the most prescribed medications in the world, is an ACE inhibitor with common side effects that can limit its use. The aim of this work is to prepare a small library of fluorescent, lisinopril-like compounds whose interaction with the ACE active site can be directly measured using fluorescence spectroscopy. Testing of such compounds is expected to shed light on the enzyme’s ability to accommodate much larger hydrophobic groups than are found in lisinopril, and to determine if the carboxylate units in the native drug are essential for binding, perhaps paving the way for future inhibitor development. Thus, several new pyrene-containing analogs were prepared using automated peptide protocols. In the presence of ACE, the putative inhibitors showed small increases in fluorescence intensity, suggesting they can enter the enzyme active site. The analogs were then challenged to inhibit ACE hydrolysis of an angiotensin I peptide containing a different (non-pyrene) fluorophore. The amidation state of the C-terminus of the lisinopril analogs appears to be a considerable factor in their ability to influence the rate of ACE hydrolysis, though additional studies are warranted.