![]() ![]() Peptoid versions of peptide ligands of three biological systems (bovine pancreatic alpha-amylase, hepatitis A virus 3C proteinase, and human immunodeficiency virus transactivator-responsive element RNA) were found with affinities comparable to those of the corresponding peptides. Preliminary data are presented on the stability of a representative oligopeptoid to enzymatic hydrolysis. A total of 15 monomers and 10 oligomers (peptoids) are described. ![]() Other steps were identical to peptide synthesis using alpha-(9-fluorenylmethoxycarbonyl)amino acids. The controlled oligomerization of the peptoid monomers was performed manually and robotically with in situ activation by either benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(pyrrolidino)phosphonium hexafluorophosphate. The monomers incorporate t-butyl-based side-chain and 9-fluorenylmethoxycarbonyl alpha-amine protection. Ramachandran-type plots were calculated and indicate a greater diversity of conformational states available for peptoids than for peptides. Peptoids, oligomers of N-substituted glycines, are described as a motif for the generation of chemically diverse libraries of novel molecules. The metabolites identified after 15 min incubation for verapamil, propranolol and cisapride are in good agreement with those reported as the major metabolites in human in vivo studies. The approach of simultaneous metabolic stability measurements and rapid identification of metabolites of drugs with high (verapamil), medium (propranolol and cisapride) and low (flunarazine) metabolic stabilities using ion-trap mass spectrometry is described. A gradient liquid chromatographic method with a run time of 6 min/injection was developed for this purpose. The data-dependent scan function mode with the ion-trap instrumentation provides the ability to measure the metabolic stability and identification of possible metabolites of a compound. As well as measuring metabolic stability in vitro using human liver microsomal preparations, the identification of possible metabolite(s) formed may play a vital role in Hit-to-Lead and Lead optimisation processes. ![]() This has stemmed from a trend in the pharmaceutical industry to use in vitro data generated from human tissue as a criterion to select compounds for further investigation. The use of in vitro drug metabolism data in the understanding of in vivo pharmacokinetic, safety and toxicity data has become a large area of scientific interest. #Nomachine unr plusCe qui nous amènera à interroger la fonction idéologique de la croyance contemporaine selon laquelle les médicaments seraient de plus en plus découverts de manière deductive et prévisible. L'histoire récente de la discipline, comme l'expérience dont témoignent ici les chercheurs que nous avons rencontrés, montrent cependant que les déductions que permettent ces modélisations sont toujours partielles et que le raisonnement analogique, le savoir accumulé, l'imagination, l'esprit d'analyse et le hasard constituent toujours les ressorts effectifs de la découverte des substances actives. On peut distinguer deux grands régimes dans la recherche pharmacologique selon que les modèles précis de la physiopathologie, de l'effet désiré et de la configuration moléculaire guident ou non la sélection des substances à tester. La recherche et la découverte de nouveaux médicaments ne sont ni assimilables à celles de lois ou de théories explicatives ou prédictives ni indépendantes des sciences biologiques et chimiques, et du savoir clinique. ![]()
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