192443-62-2Relevant academic research and scientific papers
Oxidosqualene cyclase (OSC) inhibitors for the treatment of dyslipidemia
Dehmlow, Henrietta,Ackermann, Jean,Aebi, Johannes,Blum-Kaelin, Denise,Chucholowski, Alexander,Coassolo, Philippe,Hartman, Peter,Kansy, Manfred,Maerki, Hans Peter,Morand, Olivier,Von Der Mark, Elisabeth,Panday, Narendra,Ruf, Armin,Thoma, Ralf,Schulz-Gasch, Tanja
, p. 72 - 76 (2007/10/03)
Novel inhibitors of oxidosqualene cyclase (OSC) for the treatment of dyslipidemia are reported. Starting point for the chemistry program was a set of compounds derived from a fungicide project which, in addition to high affinity for OSC from Candida albicans, also showed high affinity for the human enzyme (hOSC). Here the evaluation process of different scaffolds is outlined for two representative series, the phenyl substituted benzo[d]isothiazoles and the aminocyclohexanes. The most promising compounds derived from the latter series were further profiled in vivo and showed promising properties with respect to modulation of lipid parameters. Schweizerische Chemische Gesellschaft.
Synthesis and structure-activity studies of novel orally active non-terpenoic 2,3-oxidosqualene cyclase inhibitors
Dehmlow, Henrietta,Aebi, Johannes D.,Jolidon, Synèse,Ji, Yu-Hua,Von der Mark, Elisabeth M.,Himber, Jacques,Morand, Olivier H.
, p. 3354 - 3370 (2007/10/03)
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 ?. 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.
