RESUMEN
For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
Asunto(s)
Amidas/química , Aminobutiratos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Relación Estructura-Actividad , Amidas/antagonistas & inhibidores , Células CACO-2 , Línea Celular Tumoral , Química Farmacéutica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Diseño de Fármacos , Humanos , Hipoglucemiantes/antagonistas & inhibidores , Hipoglucemiantes/uso terapéutico , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Canales de Sodio/metabolismoRESUMEN
A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.
Asunto(s)
Aminobutiratos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Hidrocarburos Fluorados/química , Hipoglucemiantes/química , Inhibidores de Proteasas/química , Pirrolidinas/química , Administración Oral , Aminobutiratos/síntesis química , Aminobutiratos/farmacocinética , Animales , Células CACO-2 , Línea Celular Tumoral , Dipeptidil Peptidasa 4/metabolismo , Perros , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The copper enzyme galactose oxidase (GOase, EC 1.1.3.9) catalyses the oxidation of D-galactose and other primary alcohols in air to the corresponding aldehydes and hydrogen peroxide. The current mechanistic hypothesis for this two-electron redox reaction involves a Cu(I)/Cu(II) couple and the reversible oxidation of a ligating phenolate (tyrosine residue of the Tyr272-Cys228 conjugate) to a phenoxyl radical. Our approaches to functional models for galactose oxidase comprise both the use of low-molecular-weight copper complexes of a Schiff-base and sulfonamide ligands, and the synthesis/screening of combinatorial libraries. With regard to the latter, we have synthesized (by the IRORI-directed synthesis approach) peptide libraries carrying either His or the redox-active amino acids Tyr, mod-Cys (a model for the Tyr272-Cys228 conjugate) or TOAC (a TEMPO-derived alpha-amino acid) at four variable positions. After incubation with copper ions, the catalytically active library members were identified by specially designed screening methods.
Asunto(s)
Cobre/química , Galactosa Oxidasa/química , Modelos Químicos , Biomimética , Catálisis , Técnicas Químicas Combinatorias , Biblioteca de PéptidosRESUMEN
The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic, is described. After a brief introduction to the target molecule and its structural motifs, it is shown that retrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key building blocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediates are then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 24 and the thiazoline-thiazole segment 26 were synthesized by a series of reactions that included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 and the alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method was developed for the direct coupling of the labile dehydropiperidine key building block 28 to the more advanced and stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 under conditions that avoided the initially encountered destructive ring contraction process.