title: Synthesis and evaluation of pyrido[1,2-a]pyrimidines as inhibitors of nitric oxide synthases.
abstract: A series of new 3-aroylpyrido[1,2-a]pyrimidines were synthesized from aryl methyl ketones in a simple two-step procedure and evaluated as nitric oxide synthases (NOS) inhibitors. In order to perform a structure-activity relationship study, different aroyl groups were introduced in 3-position and methyl groups were introduced at different positions of the pyrimidine heterocycle. Compounds with a biphenyloyl, benzyloxybenzoyl or naphthoyl group displayed the highest inhibitory effects which were further increased by introduction of a methyl group in position 8 of the pyrido[1,2-a]pyrimidine moiety. Some of the compounds exhibited promising inhibitory effects with selectivity toward the purified inducible NOS (iNOS) and were also active against iNOS expressed in stimulated RAW 264.7 cells.
authors.affiliation: Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Ullvi
authors.initials: U
authors.lastname: Bluhm
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Boucher
authors.forename: Uwe
authors.initials: U
authors.lastname: Buss
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
authors.forename: Friederike
authors.initials: F
authors.lastname: Friedrich
authors.forename: Ulrich
authors.initials: U
authors.lastname: Girreser
authors.forename: Dieter
authors.initials: D
authors.lastname: Heber
authors.forename: Thanh
authors.initials: T
authors.lastname: Lam
authors.forename: Michel
authors.initials: M
authors.lastname: Lepoivre
authors.forename: Mojgan
authors.initials: M
authors.lastname: Rostaie-Gerylow
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wolschendorf
mesh_terms: D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005029:Ethylenediamines / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006418:Heme / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009249:NADP / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011851:Radioactivity; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013424:Sulfanilamides / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005029:Ethylenediamines; C095000:Griess reagent; D007527:Isoenzymes; D011743:Pyrimidines; D013424:Sulfanilamides; D006418:Heme; D009249:NADP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II