ABSTRACT
The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
Subject(s)
Appetite Depressants/pharmacology , Feeding Behavior/drug effects , Oleic Acids/metabolism , Oleic Acids/pharmacology , Receptors, G-Protein-Coupled/metabolism , Animals , Appetite Depressants/administration & dosage , Appetite Depressants/chemistry , Cyclic AMP/metabolism , Diet , Dose-Response Relationship, Drug , Endocannabinoids , Humans , Male , Mice , Molecular Sequence Data , Obesity/drug therapy , Oleic Acids/administration & dosage , Oleic Acids/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/genetics , Substrate Specificity , Time Factors , Yeasts/metabolismABSTRACT
A series of analogues of the peptide deformylase (PDF) inhibitor BB-3497 where the P3' amide bond was replaced with a ketone functionality is described. The in vitro antibacterial profiling of these compounds revealed that they demonstrate activity against pathogens associated with respiratory tract infections.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Infective Agents/chemistry , Enzyme Inhibitors/chemistry , Respiratory Tract Infections/enzymology , Respiratory Tract Infections/microbiology , Amidohydrolases/metabolism , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Haemophilus influenzae/drug effects , Haemophilus influenzae/enzymology , Microbial Sensitivity Tests/statistics & numerical data , Moraxella catarrhalis/drug effects , Moraxella catarrhalis/enzymology , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/enzymologyABSTRACT
Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to the methylene spacer and the P1' side chain. Enzyme inhibition and antibacterial activity data revealed that the optimum distance between the N-formyl hydroxylamine metal binding group and the P1' side chain is one unsubstituted methylene unit. Additionally, lipophilic P1' side chains that closely mimic the methionine residue in the substrate provided compounds with the best microbiological profile.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Hydroxamic Acids/chemistry , Methane/analogs & derivatives , Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hydrocarbons , Hydroxamic Acids/pharmacology , Hydroxylamine/chemistry , Inhibitory Concentration 50 , Metals/chemistry , Methane/chemistry , Microbial Sensitivity Tests , Molecular Mimicry , Oligopeptides/chemistry , Oligopeptides/pharmacology , Structure-Activity RelationshipABSTRACT
Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to both the P2' and P3' side chains. Enzyme inhibition and antibacterial activity data revealed that a variety of substituents are tolerated at the P2' and P3' positions of the inhibitor backbone. The data from this study highlights the potential for modification at the P2' and P3' positions to optimise the physicochemical properties.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Amines/chemistry , Amino Acids/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Hydroxamic Acids/chemical synthesis , Metals/chemistry , Microbial Sensitivity Tests , Molecular Mimicry , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/pharmacology , Structure-Activity RelationshipABSTRACT
A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.
