Diphenyl-pyrazole derived compounds increase survival time of mice after prion infection

Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative disorders which can be transmitted by natural infection or inoculation. TSEs include scrapie in sheep, BSE in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. The emergence of a variant form of CJD (vCJD) which has been associated to BSE, produced strong pressure to search for effective treatments with new drugs. Up to now, however, TSEs are incurable, although many efforts have been made in vitro as well as in vivo for the search for potent therapeutic and prophylactic compounds. For this purpose we analyzed a compound library consisting of 10.000 compounds with a cell-based high-throughput screening assay dealing with scrapie-infected SMB and ScN(2)A cells and identified a new class of inhibitors consisting of 3,5-diphenyl-pyrazole (DPP) derivatives. The most effective DPP derivative showed half-maximal inhibition of PrP(Sc) formation at concentrations (IC(50)) of 0.6 muM and 1.2 muM (respectively. This compound was subsequently subjected to a number of animal experiments using scrapie infected wild type C57Bl/6 and transgenic Tga 20 mice. The DPP derivative induced a significant increase of incubation time both in therapeutic and prophylactic experiments. The onset of the prion disease was delayed by 37 days after intraperitoneal and 42 days after oral application, respectively. In summary, we have shown a high in vitro efficiency of DPPs against prion infections which was substantiated in vivo for one of these compounds. These results indicate that the novel class of DPP compounds should comprise excellent candidates for future therapeutic studies



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