title: Stereoselective synthesis of a new class of potent and selective inhibitors of human Δ8,7-sterol isomerase.
abstract: Starting from Grundmann's ketone a new chemotype of inhibitors of the post-squalene part of cholesterol biosynthesis was developed. Stereoselective introduction of an angular methyl group at C-3a, followed by a plethora of functionalisations at C-4 and C-5 led to cis-configured amino alcohols as a new chemotype of inhibitors of cholesterol biosynthesis. In cell-based screening systems these compounds were identified to be selective inhibitors of human Δ8,7-sterol isomerase, inhibiting total cholesterol biosynthesis with IC50 values in the low nanomolar range. The most active compounds did not affect fungal Δ8,7-sterol isomerase (in ergosterol biosynthesis), neither showed noteworthy antimicrobial and cytotoxic effects.
authors: Ludwig-Maximilians University, Department of Pharmacy, Center for Drug Research, Butenandtstr. 5-13, 81377 Munich, Germany.
authors: Mathias
authors: M
authors: König
authors: Christoph
authors: C
authors: Müller
authors: Franz
authors: F
authors: Bracher
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D004875:Ergosterol / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D008745:Methylation; D012632:Secosteroids / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013251:Steroid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000605:Amino Alcohols; D000935:Antifungal Agents; D012632:Secosteroids; D002784:Cholesterol; D013251:Steroid Isomerases; C022669:delta(8)-delta(7)-sterol isomerase; D004875:Ergosterol