Synthesis and Structure−Activity Studies of Novel Orally Active Non-Terpenoic 2,3-Oxidosqualene Cyclase Inhibitors

Abstract

New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 A. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1.fumarate and the benzo[d]isothiazol 24.fumarate, which lowered TC by 40% and 33%, respectively.

Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

“…Inhibitors have been designed considering that the most known effective inhibitors of enzymes belonging to the family of squalene and oxidosqualene cyclases share a structure consisting in two well characterized moieties: a moiety bearing a properly shaped tertiary amino function capable of interacting with a catalytically critical Asp455 residue (human numbering) of the enzyme [4,32], and a moiety shaped so as to productively interact with the aromatic residues of the active site. The latter moiety is an isoprenic structure mimicking the squalene skeleton in azasqualene derivatives [26,33], whereas in other series of inhibitors is an electron-deficient aromatic system [4].…”

“…The latter moiety is an isoprenic structure mimicking the squalene skeleton in azasqualene derivatives [26,33], whereas in other series of inhibitors is an electron-deficient aromatic system [4]. Crystallographic studies carried on both squalene-hopene cyclase from Alicyclobacillus acidocaldarious and human OSC provided excellent explanations of the inhibitory properties of different compounds bearing an amino function [4,7,32,33].…”

“…Incorporation of [2][3][4][5][6][7][8][9][10][11][12][13][14] C] acetate into non-saponifiable lipids of human keratinocytes and mouse 3T3 fibroblasts Cells were seeded in 24-well plastic clusters. Each well received 7 £ 10 4 cells suspended in 950 mL DMEM (Dulbecco-modified Eagle medium) containing 10% (v/v) lipid-depleted serum [20].…”

“…The effects of a series of umbelliferone aminoalkyl derivatives ( Figure 2) on sterol biosynthesis was studied in mouse 3T3 fibroblasts, a cell line we previously used with other OSC inhibitors [26,27], and human keratinocytes incubated with [2][3][4][5][6][7][8][9][10][11][12][13][14] C] acetate by determining the amounts of radioactive label taken up by the biosynthetic intermediates.…”

Novel Squalene-Hopene Cyclase Inhibitors Derived from Hydroxycoumarins and Hydroxyacetophenones

“…21,22) SHC may therefore be used as a model to predict how newly designed inhibitors may interact with OSCs. Recently, the interaction of several new inhibitors of human OSC 17) with the active site of SHC was investigated by co-crystallization experiments. 23) Because comparative studies on the two enzyme types 24,25) have shown close correspondence of their inhibitor activities, we recently investigated a group of meroterpenoids that proved to be excellent inhibitors of SHC.…”