ABSTRACT
This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 µg/mL). Lack of activity against E. coli was maintained (IC50 > 20 µM and MIC > 128 µg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
Subject(s)
Acyltransferases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/chemistry , Crystallography, X-Ray , Drug Resistance, Bacterial/drug effects , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
Subject(s)
Huntingtin Protein/analysis , Huntington Disease/diagnostic imaging , Positron-Emission Tomography/methods , Protein Aggregation, Pathological/diagnostic imaging , Animals , Disease Models, Animal , Dogs , Female , Humans , Huntingtin Protein/genetics , Huntington Disease/genetics , Ligands , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred C57BL , Mutation , Peptides/genetics , Protein Aggregation, Pathological/genetics , Radiopharmaceuticals/analysis , Rats, Sprague-DawleyABSTRACT
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyridines/chemistry , Binding Sites , Crystallography, X-Ray , Kinetics , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/metabolism , Structure-Activity Relationship , Sulfones/chemistryABSTRACT
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Benzothiazoles/chemical synthesis , Crystallography, X-Ray , Drug Design , Humans , Mice , Models, Molecular , Protein-Tyrosine Kinases/chemistry , Signal Transduction , Structure-Activity RelationshipABSTRACT
An efficient total synthesis of the novel botryococcene-related hydrocarbon 7,11-cyclobotryococca-5,12,26-triene is reported that uses, as a key step, an oxidative radical cyclization of a 4-pentenyl malonate for the synthesis of a [3.3.0]-bicyclic gamma-lactone.
ABSTRACT
The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5-hydroxytryptamine (5-HT(1A)) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats. Ex vivo radioligand binding was used to estimate brain monoamine transporter occupancy. Sibutramine (1-10 mg/kg p.o.) dose-dependently reduced food intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5-HT(1A) agonist F-11440 (2.5 mg/kg p.o.) attenuated sibutramine-induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did not alter food intake alone, but each reduced food intake when combined with F-11440. These results suggest that sibutramine-induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5-HT(1A) activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5-HT(1A) activation. Hence increased synaptic serotonin, via serotonin reuptake inhibition or 5-HT(1A) activation, together with increased NA, would appear to produce hypophagia. Thus weight loss with minimal cardiovascular risk could be achieved by 5-HT(1A) activation combined with NA transporter blockade.
Subject(s)
Appetite Depressants/pharmacology , Blood Pressure/drug effects , Cyclobutanes/pharmacology , Eating/drug effects , Heart Rate/drug effects , Receptor, Serotonin, 5-HT1A/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Animals , Dose-Response Relationship, Drug , Fluoxetine/analogs & derivatives , Fluoxetine/pharmacology , Male , Models, Animal , Morpholines/pharmacology , Norepinephrine/pharmacology , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Reboxetine , Serotonin 5-HT1 Receptor Agonists , Triazines/pharmacologyABSTRACT
A solid-phase synthesis of new N-substituted valienamines has been developed and new synthesis of (+/-)-conduramine F-1, (-)-conduramine F-1, and (+)-ent-conduramine F-1 is presented, together with the preparation of N-benzylated conduramines F-1. N-Benzylation of both valienamine and (+)-ent-conduramine F-1 improves their inhibitory activity toward alpha-glucosidases significantly. The additional hydroxymethyl group makes valienamine derivatives more active than their (+)-ent-conduramine F-1 analogues.
Subject(s)
Cyclohexanols/pharmacology , Cyclohexylamines/pharmacology , Enzyme Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors , Hexosamines/pharmacology , Cyclohexanols/chemical synthesis , Cyclohexanols/chemistry , Cyclohexenes , Cyclohexylamines/chemical synthesis , Cyclohexylamines/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hexosamines/chemical synthesis , Hexosamines/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
1,6-Dideoxygalactostatin, the mirror image of 1-deoxy-L-fuconojirimycin, was efficiently prepared from 2,3-O-isopropylidene-L-lyxonolactone in four steps and evaluated as a glycosidase inhibitor.
