title: Lathosterol side chain amides: a new class of human lathosterol oxidase inhibitors.
abstract: Inhibition of cholesterol biosynthesis offers the opportunity for treatment of cardiovascular diseases. Numerous enzymes are involved in the post-squalene part of this biosynthesis, and selective inhibitors for almost all of the enzymes involved there have been described in literature. The only exception is the enzyme lathosterol oxidase (EC 1.14.21.6), for which up to now no selective inhibitor has been found. Up to date only triarimol has been reported as a weak inhibitor. In this paper we report on lathosterol side chain amides as a new class of selective lathosterol oxidase inhibitors. To study the influence of different sterol amides on inhibition of this enzyme, numerous compounds were prepared and the sterol patterns resulting from incubation of HL 60 cells with these enzyme inhibitors were monitored in a whole cell screening assay by means of GC/MS analysis. Small alkyl residues at the amide nitrogen (hydrogen and methyl) lead to an inhibition of the enzyme Delta24-reductase, the N-ethyl and N-propyl derivatives show a dual action, inhibiting both Delta24-reductase and lathosterol oxidase. Lathosterol-derived amides with larger substituents (butyl, isobutyl, tert-butyl, pentyl) at the amide nitrogen were found to be selective inhibitors of lathosterol oxidase. The corresponding 3beta-acetoxy derivatives showed comparable activities and can be considered as prodrugs, since they are transformed into the 3beta-hydroxy derivatives under the test conditions, as proven by HPLC analysis.
authors.affiliation: Department Pharmazie Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Munich, Germany. martin.giera@cup.uni-muenchen.de
authors.forename: Martin
authors.initials: M
authors.lastname: Giera
authors.forename: Delphine
authors.initials: D
authors.lastname: Renard
authors.forename: Florian
authors.initials: F
authors.lastname: Plössl
authors.forename: Franz
authors.initials: F
authors.lastname: Bracher
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D002784:Cholesterol / Q000737:chemistry* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D018922:HL-60 Cells; D006801:Humans; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; C033144:lathosterol delta-5-dehydrogenase; C001521:lathosterol; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors