Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropyridin-2-imines

• Published in: Bioorganic & medicinal chemistry letters 2002-09, Vol.12 (17), p.2291-2294
• Main Authors: Kawanaka, Yasufumi, Kobayashi, Kaoru, Kusuda, Shinya, Tatsumi, Tadashi, Murota, Masanori, Nishiyama, Toshihiko, Hisaichi, Katsuya, Fujii, Atsuko, Hirai, Keisuke, Naka, Masao, Komeno, Masaharu, Nakai, Hisao, Toda, Masaaki
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Bones, joints and connective tissue. Antiinflammatory agents; Dihydropyridines - chemical synthesis; Dihydropyridines - pharmacokinetics; Dihydropyridines - pharmacology; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Imines - chemical synthesis; Imines - pharmacokinetics; Imines - pharmacology; Lipopolysaccharides - administration & dosage; Maximum Tolerated Dose; Medical sciences; Mice; Nitric Oxide - blood; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase Type II; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00455-9

Dihydropyridin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide inhibition assay. Compounds 1, 4, 5 and 7– 11 exhibited potent activity in the inducible nitric oxide (iNOS) inhibition assay. Of these 5, 6, 9 and 10 showed 5- to 11-fold increases in isoform selectivity. Compounds 1, 5, 9 and 10 showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 5 also showed good bioavailability (BA) when given orally. The dihydropyridin-2-imines, 1, 5, 9 and 10 were identified as potent inhibitors of inducible nitric oxide.