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We examined the effect of the pyrido[1, 2-a]pyrimidines 1 on nNOS and determined the selectivity towards the inducible iNOS ; and endothelial NOS eNOS ; . Most of the pyrido[1, 2-a]pyrimidines 1 inhibited NOsynthases in a concentration dependent manner. By synthesis of more than 50 derivatives and testing their activity clear structure-activity-relationships could be developed also with respect to nNOS selectivity. Testing of the NOSs revealed that R1 should be a naphthyl- or biphenylring, ii ; R2 should be a hydrogen atom and iii ; a methyl function in R3 is favourable. By development of new hplc-methods we could also exclude that potential impurities of 2-aminopyridines 2 used as starting material and known to be potent but also toxic inhibitors of NO-synthases [3] are responsible for the measured activities. [1] L. H. Lassen et al., Eur. J. Clin. Pharmacol. 1996, 49, 335-339. [2] U. Girreser et al., Synlett 1998, 263-264. [3] R. Boer et al., Mol. Pharmacol. 2000, 58 5 ; , 1026-1033.
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Melman KL, Rocklin RE, Rosenkranz RP. Autacoids as modulators of the inflammatory and immune response. J Med 1981; 71: 100-106. Meyerhoff J. Familial Mediterranean fever: report of a large family, review of the literature, and discussion of the frequenty of amyloidosis. Medicine 1980; 59: 66-77. Padeh S, Brezniak N, Zemer D, Pras E, Livneb A, Langevitz P, Migdal A, Pras M, Passwell JH. Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr 1999; 135: 98-101. Prieur AM, Griscelli C. Nosologic aspects of systemic forms of very early onset juvenile arthritis. A propos of 17 cases. Ann Pediatr Paris ; 1983; 30: 565-569. Raimann HA, de Berardinis CT. Periodic cyclic ; neutropenia, an entity. Blood 1949; 4: 1109-1116. Raimann HA. Periodic disease: a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. JAMA 1948; 136: 239-244. Rakover Y, Adar H, Tal I, Lang Y, Kedar A. Behet disease: long-term follow-up of three children and review of the literature. Pediatrics 1989; 83: 66-77. Reeves WG, Mitchell JRA. Hyperimmunoglobulinaemia D and periodic fever. Lancet 1984; 1: 1463-1464. Scholl PR. Periodic fever syndromes. Curr Opin Pediatr 2000; 12: 563-566. Scimeca PG, James-Herry AG, Weinblatt ME. Atypical PFAPA syndrome periodic fever, aphthous stomatitis, pharyngitis, adenitis ; in a young girl with Fanconi anemia. J Pediatr Hematol Oncol 1996; 18: 159-161.
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