Synthesis and evaluation of pyrido[1,2-a]pyrimidines as inhibitors of nitric oxide synthases.

Ullvi Bluhm, Jean-Luc Boucher, Uwe Buss, Bernd Clement, Friederike Friedrich, Ulrich Girreser, Dieter Heber, Thanh Lam, Michel Lepoivre, Mojgan Rostaie-Gerylow, Ulrich Wolschendorf

Index: Eur. J. Med. Chem. 44 , 2877-87, (2009)

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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.