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1.
Bioorg Med Chem Lett ; 20(2): 694-9, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19959358

ABSTRACT

Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.


Subject(s)
Amines/chemistry , Carbamates/chemistry , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Binding Sites , Blood Pressure/drug effects , Carbamates/chemical synthesis , Carbamates/pharmacokinetics , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Humans , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Rats, Transgenic , Renin/blood , Renin/metabolism , Structure-Activity Relationship
3.
Nat Biotechnol ; 20(5): 478-83, 2002 May.
Article in English | MEDLINE | ID: mdl-11981561

ABSTRACT

As the global threat of drug- and antibiotic-resistant bacteria continues to rise, new strategies are required to advance the drug discovery process. This work describes the construction of an array of Escherichia coli strains for use in whole-cell screens to identify new antimicrobial compounds. We used the recombination systems from bacteriophages lambda and P1 to engineer each strain in the array for low-level expression of a single, essential gene product, thus making each strain hypersusceptible to specific inhibitors of that gene target. Screening of nine strains from the array in parallel against a large chemical library permitted identification of new inhibitors of bacterial growth. As an example of the target specificity of the approach, compounds identified in the whole-cell screen for MurA inhibitors were also found to block the biochemical function of the target when tested in vitro.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Evaluation, Preclinical/methods , Oligonucleotide Array Sequence Analysis , Alkyl and Aryl Transferases/metabolism , Alleles , Escherichia coli/metabolism , Inhibitory Concentration 50 , Kinetics , Models, Genetic , Plasmids/metabolism , Protein Conformation , Recombination, Genetic , Time Factors
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