Design and Synthesis of A‐Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors

Abstract

Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO-1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O-acyltransferase 2 (SOAT2). To aid in the development of new cholesterol-lowering or anti-atherosclerotic agents, new A-ring simplified pyripyropene A analogues have been designed and synthesized based on total synthesis, and the results of structure-activity relationship studies of pyripyropene A. Among the analogues, two A-ring simplified pyripyropene A analogues exhibited equally efficient SOAT2 inhibitory activity to that of natural pyripyropene A. These new analogues are the most potent and selective SOAT2 inhibitors to be used as synthetic compounds and attractive seed compounds for the development of drug for dyslipidemia, including atherosclerotic disease and steatosis.

Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists

“…SOAT2 is an enzyme that converts cholesterol to cholesterol esters and plays an important role in intestinal cholesterol absorption, lipoprotein assembly, and cholesterol metabolism. Another isoform, SOAT1 (sometimes incorrectly called ACAT1), is much more widely expressed and plays a critical role in macrophages. , Based on its role in cholesterol reabsorption, SOAT2 was identified as a therapeutic target for atherosclerosis, as increased expression of Soat2 is an indicator of increased risk of development of CVD. − While increased Soat2 expression is associated with increased risk of CVD, the opposite appears to be the case for Soat1 . Knockout of Soat1 in macrophages leads to increased foam cell formation and atherosclerosis, while knockout of Soat2 in mice fed a high-fat and high-cholesterol diet are resistant to the development of hypercholesterolemia or atherosclerosis.…”

Structural Simplification of Natural Products

“…Then, the structural simplification was performed to give new A ring-simplified pyripyropene A analogues based on the results of the SAR studies. Among these simplified analogues, 60 showed excellent SOAT2 inhibitory activity (IC 50 = 0.07 μM) with high isozyme selectivity over SOAT1, and its activity was comparable to that of natural pyripyropene A …”

“…Among these simplified analogues, 60 showed excellent SOAT2 inhibitory activity (IC 50 = 0.07 μM) with high isozyme selectivity over SOAT1, and its activity was comparable to that of natural pyripyropene A. 147 60 was considered to be the most potent and selective synthetic inhibitor of SOAT2 and an attractive candidate for further development.…”

“…Pyripyropene A ( 59 , Figure ), isolated from the culture broth of Aspergillus fumigatus strain FO-1289, is a strong and selective inhibitor of sterol O -acyltransferase 2 (SOAT2) (IC 50 = 0.07 μM), − which is an important target for the treatment of hypercholesterolemia and atherosclerosis. , In the pursuit of new cholesterol-lowering or antiatherosclerotic agents, Nagamitsu’s group reported the first total synthesis of pyripyropene A in 2011 . Then, the structural simplification was performed to give new A ring-simplified pyripyropene A analogues based on the results of the SAR studies.…”

Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential

“…By extending earlier study findings on the SOAT2 selectivity of PPPA, Ohtawa et al published the synthesis and biological evaluation of novel A-ring-simplified analogs of PPPA ( 130 – 135 ) in 2018 . As a result, new PPPA derivatives were generated semisynthetically.…”