ABSTRACT
The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.
Subject(s)
Molecular Probes/pharmacology , Nuclear Proteins/metabolism , Quinazolinones/pharmacology , Sulfonamides/pharmacology , Transcription Factors/antagonists & inhibitors , Cell Cycle Proteins , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Probes/chemical synthesis , Molecular Structure , Nuclear Proteins/antagonists & inhibitors , Protein Binding , Quinazolinones/chemical synthesis , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Interferons/agonists , Toll-Like Receptor 7/agonists , Aldehyde Oxidase/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Discovery , Drug Evaluation, Preclinical , Hepacivirus/physiology , Hepatitis C/virology , Humans , Injections, Intravenous , Interferon Inducers/chemical synthesis , Interferon Inducers/chemistry , Interferon Inducers/pharmacokinetics , Interferon Inducers/pharmacology , Microsomes, Liver/metabolism , Molecular Targeted Therapy , Molecular Weight , Purines/chemical synthesis , Purines/metabolism , Rats , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/drug effects , Purines/chemistry , RNA Virus Infections/drug therapy , Toll-Like Receptor 7/agonists , Administration, Oral , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/therapeutic use , Drug Design , Mice , Models, Animal , Purines/pharmacokinetics , Purines/therapeutic use , Rats , Structure-Activity Relationship , Toll-Like Receptor 7/metabolismABSTRACT
The rhodium-catalysed conjugate addition of arylboronic acids to an enantiopure acceptor derived from (R)-S-methylcysteine proceeds under substrate control to provide a range of functionalised phenylalanine derivatives with excellent stereocontrol via a highly diastereoselective protonation.
Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Boronic Acids/chemistry , Rhodium/chemistry , Catalysis , Crystallography, X-Ray , Models, Chemical , Oxazolidinones/chemistry , Protons , StereoisomerismABSTRACT
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Norepinephrine , Piperazines/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Urinary Incontinence, Stress/drug therapy , Adrenergic Uptake Inhibitors/metabolism , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Dogs , Humans , Piperazines/metabolism , Piperazines/pharmacology , Selective Serotonin Reuptake Inhibitors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Structure-Activity RelationshipSubject(s)
Pyrrolidines/chemistry , Catalysis , Crystallography, X-Ray , Molecular Structure , Rhodium/chemistry , StereoisomerismABSTRACT
The appropriate choice of organometallic nucleophile enables the straightforward preparation of different stereoisomers of 2-substituted pyrrolizidinones utilising the rhodium-catalysed 1,4-addition reaction.
ABSTRACT
The cationic rhodium complex [Rh(cod)2][BF4] effectively catalyses the 1,4-addition of organotrialkoxysilanes to alpha-substituted acrylic esters. The reactions are promoted by heating in an oil-bath or more conveniently in a microwave reactor allowing rapid access to a useful range of functionalised products including 2-alkyl succinates and alpha-amino acid derivatives.
Subject(s)
Esters/chemistry , Organic Chemicals/chemical synthesis , Rhodium , Silanes/chemistry , Catalysis , Magnetic Resonance Spectroscopy , Metals , Models, Molecular , Molecular Conformation , Naphthalimides/chemistryABSTRACT
The synthesis and structure-activity relationships of a novel series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake is described. Two compounds possessed comparable in vitro profiles to the dual reuptake inhibitor duloxetine.
Subject(s)
Norepinephrine/chemistry , Piperazines/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/chemistry , Amines/chemistry , Chemistry, Pharmaceutical/methods , Drug Design , Duloxetine Hydrochloride , Humans , Models, Chemical , Serotonin Plasma Membrane Transport Proteins/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.
