RESUMEN
With the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach with implications for salvage and preexposure prophylactic regimens, as well as topical microbicides. Using the combination of a field-derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors.
Asunto(s)
Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Conformación MolecularRESUMEN
Structure-based methods were used to design beta-sulfone 3,3-piperidine hydroxamates as TACE inhibitors with the aim of improving selectivity for TACE versus MMP-13. Several compounds in this series were synthesized and evaluated in enzymatic and cell-based assays. These analogs exhibit excellent in vitro potency against isolated TACE enzyme and show good selectivity for TACE over the related metalloproteases MMP-2, -13, and -14.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Proteína ADAM17 , Diseño de Fármacos , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/química , Modelos MolecularesRESUMEN
By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.