A. Polak-Wyss

Bio: A. Polak-Wyss is an academic researcher from Hoffmann-La Roche. The author has contributed to research in topics: 2,3-Oxidosqualene & Ergosterol. The author has an hindex of 1, co-authored 1 publications receiving 6 citations.

Inhibitors of 2,3-Oxidosqualene-Lanosterol Cyclase as Antifungal Agents

Abstract: Most known antifungals act on enzymes involved in the biosynthesis of ergosterol, the main sterol in fungi 2,3-Oxidosqualene-lanosterol cyclase is one of these enzymes; several inhibitors of the enzyme are known, which however have poor antifungal activity A simple approach based on mechanistic considerations led to the synthesis of potent bifunctional inhibitors of 2,3-oxidosqualene-lanosterol cyclase These amino-ketones represent the first cyclase inhibitors which also show an effective in vitro activity against a wide range of medically important fungi A cell-free assay is presented, which allows accurate determination of IC50-values

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.

A novel series of 4-piperidinopyridine and 4-piperidinopyrimidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase.

Abstract: A novel series of 4-piperidinopyridines and 4-piperidinopyrimidines showed potent and selective inhibition of rat 2,3-oxidosqualene cyclase-lanosterol synthase (OSC) (e.g. 26 IC(50) rat = 398 +/- 25 nM, human = 112 +/- 25 nM) and gave selective oral inhibition of rat cholesterol biosynthesis (26 ED(80) = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin ED(80) = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a significantly lower pK(a) than the corresponding pyridine or the previously reported quinuclidine OSC inhibitor series. This indicates that other novel OSC inhibitors may be found in analogues of this series across a broader pK(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agents for the treatment of cardiovascular disease.

Use of phenylalkylamines for producing cholesterol lowering agents

Abstract: Use of compounds of the formula in which one of R and R is C1-7-alkyl and the other is C1-7-alkyl or C2-6-alkenylmethyl, L is C1-11-alkylene or C2-11-alkenylene which is optionally bonded via an O atom to the phenyl group, or L is 1,4-phenylene, n is 0 or, if L contains an O atom, n is 0 or 1, Q is C1-7-alkyl, C2-10-alkenyl or a group of the formula Q': R is H, halogen, CF3, CN or NO2, R and R are H, C1-4-alkyl or halogen, and R is H or, if R is H, H or halogen, and their pharmaceutically acceptable acid addition salts for producing cholesterol-lowering medicinal agents, and compounds covered by formula I.

Methods related to metabolism of parasites and mycobacteria

Abstract: The present invention relates to the field of microorganism metabolism. In one aspect, the present invention relates to parasite and mycobacterial steroid compound biosynthesis, including methods to inhibit the steroid compound biosynthesis. The present invention therefore relates broadly to microbiology, pharmaceutical chemistery, and disease treatments.