A glutaminyl cyclase (QC) fragment library was in silico selected by disconnection of the structure of known QC inhibitors and by lead-like 2D virtual screening of the same set. The resulting fragment library (204 compounds) was acquired from commercial suppliers and pre-screened by differential scanning fluorimetry followed by functional in vitro assays. In this way, 10 fragment hits were identified ([Formula: see text]5 % hit rate, best inhibitory activity: 16 [Formula: see text]). The in vitro hits were then docked to the active site of QC, and the best scoring compounds were analyzed for binding interactions. Two fragments bound to different regions in a complementary manner, and thus, linking those fragments offered a rational strategy to generate novel QC inhibitors. Based on the structure of the virtual linked fragment, a 77-membered QC target focused library was selected from vendor databases and docked to the active site of QC. A PubChem search confirmed that the best scoring analogues are novel, potential QC inhibitors.
Fused pyrimidine derivativesFused pyrimidine derivatives R 0515 A Novel Orally Active Inhibitor of HLE. -The synthesis of compound (IX), a potential orally active HLE inhibitor for the treatment of inflammatory bronchopulmonary diseases such as COPD and chronic bronchitis, is presented. Ex vivo experiments in mice and the in vivo acute HLE induced mouse lung haemorrhage model demonstrate the remarkable oral activity of this new substance. -(VARGA*, M.; KAPUI, Z.; BATORI, S.; NAGY, L. T.; VASVARI-DEBRECZY, L.; MIKUS, E.; URBAN-SZABO, K.; ARANYI, P.; Eur. J. Med. Chem. 38 (2003) 4, 421-425; Discovery Res., CHINOIN Co. Ltd., H-1045 Budapest, Hung.; Eng.) -H. Haber 37-130
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