title: Synthesis and biological evaluation of first N-alkyl syn dimeric 4-aryl-1,4-dihydropyridines as competitive HIV-1 protease inhibitors.
abstract: A first series of novel N-alkyl substituted syn dimeric 4-aryl-1,4-dihydropyridines 12--17 have been synthesised and evaluated as HIV-1 protease inhibitors in in vitro assays. While the N-methyl derivatives 12 and 13 were almost inactive, with IC(50)-values of about 225 microM, the N-benzyl compounds with varied ester groups all exhibited stronger activities, with IC(50)-values of 11--12 microM for the presently best compounds 16 and 17 with ethyl ester functions. The type of HIV-1 protease inhibition of the novel inhibitors was characterised as competitive. With the increase of observed activity from N-methyl derivatives to N-benzyl compounds the binding mode may correspond to that of cyclic ureas with hydrophobic interactions of the four aromatic residues to the S1/S1' and S2/S2' regions of HIV-1 protease.
authors.affiliation: Department of Pharmacy, Martin-Luther University Halle--Wittenberg, Wolfgang-Langenbeck Strasse 4, D-06120 Halle, Germany. hilgeroth@pharmazie.uni-halle.de
authors.forename: A
authors.initials: A
authors.lastname: Hilgeroth
authors.forename: A
authors.initials: A
authors.lastname: Billich
authors.forename: H
authors.initials: H
authors.lastname: Lilie
mesh_terms: D001671:Biochemistry / Q000379:methods; D003503:Cyclobutanes / Q000737:chemistry* / Q000494:pharmacology*; D019281:Dimerization; D004353:Drug Evaluation, Preclinical; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D003503:Cyclobutanes; D017320:HIV Protease Inhibitors; D011725:Pyridines; C438727:diethyl -1,5-dibenzyl-1,5,8,8b-tetrahydro-4a,8a-dihydroxymethyl-4,8-diphenyl-cyclobuta(1,2b,3,4b')dipyridine-3,7(4H,4bH)dicarboxylate; C438726:diethyl 1,5-dibenzyl-1,5,8,8b-tetrahydro-4a,8a-dihydroxymethyl-4,8-bis(4-methoxyphenyl)-cyclobuta(1,2b,3,4b')dipyridine-3,7(4H,4bH)dicarboxylate; D016333:HIV Protease