The author of 《Dual-reporter high-throughput screen for small-molecule in vivo inhibitors of plasminogen activator inhibitor type-1 yields a clinical lead candidate》 were Reinke, Ashley A.; Li, Shih-Hon; Warnock, Mark; Shaydakov, Maxim E.; Guntaka, Naga Sandhya; Su, Enming J.; Diaz, Jose A.; Emal, Cory D.; Lawrence, Daniel A.. And the article was published in Journal of Biological Chemistry in 2019. Safety of Ethyl oxalyl monochloride The author mentioned the following in the article:
Plasminogen activator inhibitor type-1 (PAI-1) is a serine protease inhibitor (serpin) implicated in numerous pathol. processes, including coronary heart disease, arterial and venous thrombosis, and chronic fibrotic diseases. These associations have made PAI-1 an attractive pharmaceutical target. However, the complexity of the serpin inhibitory mechanism, the inherent metastability of serpins, and the high-affinity association of PAI-1 with vitronectin in vivo have made it difficult to identify pharmacol. effective small-mol. inhibitors. Moreover, the majority of current small-mol. PAI-1 inhibitors are poor pharmaceutical candidates. To this end and to find leads that can be efficiently applied to in vivo settings, we developed a dual-reporter high-throughput screen (HTS) that reduced the rate of nonspecific and promiscuous hits and identified leads that inhibit human PAI-1 in the high-protein environments present in vivo. Using this system, we screened >152,000 pure compounds and 27,000 natural product extracts (NPEs), reducing the apparent hit rate by almost 10-fold compared with previous screening approaches. Furthermore, screening in a high-protein environment permitted the identification of compounds that retained activity in both ex vivo plasma and in vivo. Following lead identification, subsequent medicinal chem. and structure-activity relationship (SAR) studies identified a lead clin. candidate, MDI-2268, having excellent pharmacokinetics, potent activity against vitronectin-bound PAI-1 in vivo, and efficacy in a murine model of venous thrombosis. This rigorous HTS approach eliminates promiscuous candidate leads, significantly accelerates the process of identifying PAI-1 inhibitors that can be rapidly deployed in vivo, and has enabled identification of a potent lead compound The experimental process involved the reaction of Ethyl oxalyl monochloride(cas: 4755-77-5Safety of Ethyl oxalyl monochloride)
Ethyl oxalyl monochloride(cas: 4755-77-5) belongs to acyl chlorides. In the laboratory, acyl chlorides are generally prepared by treating carboxylic acids with thionyl chloride (SOCl2). The reaction is catalyzed by dimethylformamide and other additives.Safety of Ethyl oxalyl monochloride
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