ABSTRACT
The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.
Subject(s)
Antidepressive Agents/chemistry , Neurokinin-1 Receptor Antagonists/chemistry , Receptors, Neurokinin-1/chemistry , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Behavior, Animal/drug effects , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Dogs , Female , Gerbillinae , Half-Life , Humans , Male , Models, Molecular , Molecular Conformation , Neurokinin-1 Receptor Antagonists/chemical synthesis , Neurokinin-1 Receptor Antagonists/pharmacokinetics , Piperazines/chemistry , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacokinetics , Protein Binding , Rats , Receptors, Neurokinin-1/genetics , Receptors, Neurokinin-1/metabolismABSTRACT
The introduction of the isoxazole ring as bioisosteric replacement of the acetyl group of anatoxin-a led to a new series of derivatives binding to nicotinic acetylcholine receptors. Bulkier substitutions than methyl at the 3 position of isoxazole were shown to be detrimental for the activity. The binding potency of the most interesting compounds with α1, α7 and α3ß4 receptor subtypes, was, anyway, only at micromolar level. Moreover, differently from known derivatives with pyridine, isoxazole condensed to azabicyclo ring led to no activity.
Subject(s)
Receptors, Nicotinic/metabolism , Tropanes/chemistry , Chemistry Techniques, Synthetic , Cyanobacteria Toxins , Dose-Response Relationship, Drug , Ligands , Molecular Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
Subject(s)
Drug Discovery , Piperidines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Sleep Wake Disorders/drug therapy , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Orexin Receptors , Piperidines/chemical synthesis , Piperidines/chemistry , Rats , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/chemistry , Heptanes/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Dopamine Plasma Membrane Transport Proteins/chemistry , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/pharmacology , Heptanes/chemical synthesis , Heptanes/pharmacology , Humans , Norepinephrine Plasma Membrane Transport Proteins/chemistry , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Protein Binding , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.
Subject(s)
Benzodiazepinones/pharmacology , Receptor, Cholecystokinin B/antagonists & inhibitors , Animals , Benzodiazepinones/chemical synthesis , Benzodiazepinones/chemistry , Dogs , Guinea Pigs , Mice , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
Liquid chromatography-NMR (LC-NMR) spectroscopy was used to obtain detailed information regarding the structure of the major bulk drug impurities present in GW597599 (vestipitant). The one-dimensional (1)H LC-NMR experiments were performed in both continuous and stop-flow modes on a sample of GW597599 (vestipitant) enriched with mother liquor impurities. The information derived from both LC-NMR and LC-MS data provided the structural information of all major impurities. The full characterisation of the impurities by high-resolution NMR spectroscopy was ultimately performed on appropriately synthesised compounds.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drug Contamination , Drug Industry/methods , Magnetic Resonance Spectroscopy/methods , Neurokinin-1 Receptor Antagonists , Piperidines/analysis , Fluorobenzenes , Mass Spectrometry/methods , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , SolutionsABSTRACT
Following the disclosure of 3-(1,2,2-trimethylpropyl) 4-[3,5-dimethyl-2-propyloxycarbonyl]pyrrolecarboxylate as a potent and selective mGluR1 non-competitive antagonist, the role and the importance of the pyrrole template were investigated. Different aromatic moieties were investigated as possible bio-isosteric replacement of the original scaffold and some of them were shown to be partially able to mimic the properties of the original pyrrole ring.
Subject(s)
Analgesics, Non-Narcotic/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Analgesics, Non-Narcotic/pharmacology , Animals , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Binding, Competitive/drug effects , CHO Cells , Cricetinae , Esters/chemical synthesis , Esters/pharmacology , Inhibitory Concentration 50 , Mice , Nociceptors/drug effects , Pain Measurement , Pyrroles/pharmacology , Rats , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/genetics , Spinal Cord/drug effects , Spinal Cord/metabolism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
A series of benzoazepine derivatives, bearing suitable substituents at the C-3 position, was designed and evaluated by superimposition with the pharmacophore model of the glycine binding site. To fully explore the SAR of this class of compounds and to allow the preparation of new different compounds at the C-3 position, appropriate synthetic routes were set up. The benzoazepines were evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. This further analysis confirmed the preliminary results previously reported and that compound 27 is the most promising compound (Ki=32 nM, ED(50)=0.09 mg/kg, i.v.) in this series. Significant neuroprotective effect was observed after both pre- and post-ischaemia administration in the MCAo model. In particular, after post-ischaemia administration, it was found to be still effective when the administration was delayed up to 6 h after occlusion of the middle cerebral artery.
Subject(s)
Anticonvulsants/chemical synthesis , Azepines/chemical synthesis , Neuroprotective Agents/chemical synthesis , Receptors, Glycine/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Arterial Occlusive Diseases/complications , Azepines/chemistry , Azepines/pharmacology , Binding Sites , Brain Ischemia/drug therapy , Brain Ischemia/etiology , Male , Mice , Middle Cerebral Artery , Models, Molecular , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(-)-2 and (S)-(+)-2, displaying α2C-adrenoreceptor (AR) agonism/α2A-AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT1A receptor (5-HT1A-R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as α2C-AR agonists/α2A-AR antagonists/5-HT1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction.
ABSTRACT
The aggregation behaviour of casopitant mesylate, a new NK1 antagonist drug, was investigated by means of NMR spectroscopy and surface tension measurements. The critical micelle concentration (CMC) in glycine buffer at pH 3.5 was determined by analyzing the (1)H NMR chemical shifts variation and the surface tension in function of the concentration in a series of solutions. The temperature dependence of the CMC was also evaluated by NMR spectroscopy as well as the thermodynamic parameters contributing to the aggregation discussed. Surface tension measurements were conducted as well in the formulation conditions, e.g. in the presence of sodium chloride.
Subject(s)
Chemistry, Pharmaceutical/methods , Magnetic Resonance Spectroscopy/methods , Neurokinin-1 Receptor Antagonists , Piperazines/pharmacology , Piperidines/pharmacology , Drug Design , Humans , Hydrogen-Ion Concentration , Micelles , Models, Chemical , Piperazine , Piperazines/chemistry , Surface Properties , Technology, Pharmaceutical/methods , Temperature , ThermodynamicsABSTRACT
During late phase development of the selective NK1 receptor antagonist casopitant mesylate, a de-fluorinated impurity was discovered and quantified by an orthogonal analytical approach, using NMR and LC-MS. A dedicated (19)F NMR method was initially developed for first line identification and semi-quantification of the impurity. Subsequently, a more accurate quantification was achieved by means of a selective normal-phase LC-MS method, which was fully validated. The results obtained on the development batches of the drug substance were used by the project team to set up a suitable control strategy and ultimately to ensure patient safety and the progression of the project.
Subject(s)
Chemistry, Pharmaceutical/methods , Drug Contamination , Fluorine/chemistry , Piperazines/analysis , Piperidines/analysis , Chemistry Techniques, Analytical , Chromatography, Liquid/methods , Halogenation , Magnetic Resonance Spectroscopy/methods , Mass Spectrometry/methods , Models, Chemical , Pharmaceutical Preparations/chemistry , Quality Control , Reproducibility of ResultsABSTRACT
A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.
Subject(s)
Brain/drug effects , Brain/metabolism , Depressive Disorder/drug therapy , Neurokinin-1 Receptor Antagonists , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , Behavior, Animal/drug effects , CHO Cells , Cricetinae , Cricetulus , Depressive Disorder/metabolism , Drug Discovery , Gerbillinae , Half-Life , Humans , Magnetic Resonance Spectroscopy , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperidines/chemistry , Piperidines/pharmacokinetics , Regression Analysis , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared , StereoisomerismABSTRACT
Vestipitant (1) is a novel NK1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The first synthetic step comprised a Grignard synthesis. An impurity was identified and initially expected to be a symmetric biphenyl. This paper reports the work to synthesise the supposed structure and the spectroscopic analyses (LC-NMR and HR-NMR) to correctly identify the real structure and understand the chemical pathway of the impurity.
Subject(s)
Biphenyl Compounds/chemistry , Drug Contamination , Magnetic Resonance Spectroscopy/methods , Neurokinin-1 Receptor Antagonists , Piperidines/chemistry , Chromatography, High Pressure Liquid , Fluorobenzenes , Piperidines/chemical synthesisABSTRACT
Herein we report a detailed description of the structure-activity relationships for a novel series of "C-linked" 1,2,4-triazolylazabicyclo[3.1.0]hexanes. These derivatives are endowed with very high in vitro affinity and selectivity for the dopamine D(3) receptor. An optimization with respect to undesired affinity toward the hERG potassium channel is also reported. Members of this compound series also show excellent in vitro and in vivo pharmacokinetic properties.
Subject(s)
Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Hexanes/chemistry , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/chemistry , Animals , Binding Sites , Computer Simulation , Hexanes/chemical synthesis , Hexanes/pharmacokinetics , Humans , Rats , Receptors, Dopamine D3/metabolism , Structure-Activity RelationshipABSTRACT
A multi-technique approach was applied in order to fully characterize four low-level unknown impurities of GW876008, a novel CRF(1) receptor antagonist. Liquid chromatography (LC)-NMR spectroscopy was used in combination with LC-MS to obtain detailed information regarding the structure of the two major impurities present in batches of GW876008 and observed in the first synthetic scale-up for preclinical use. Two additional impurities were unexpectedly found at greater levels in a large scale synthesis for clinical use and their structure was elucidated by means of high resolution (HR)-MS and HR-NMR, after a small scale preparative HPLC purification step. This structural information was useful in terms of shedding light on the typical impurity profile of this new chemical entity with the aim to support the early development package for Phase I clinical studies.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/analysis , Chromatography, High Pressure Liquid/methods , Drug Contamination , Magnetic Resonance Spectroscopy/methods , Pyrazoles/analysis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Spectrometry, Mass, Electrospray Ionization/methods , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Pyrazoles/chemistryABSTRACT
A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.
Subject(s)
Azabicyclo Compounds/chemical synthesis , Models, Molecular , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/chemical synthesis , Animals , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , CHO Cells , Catalytic Domain , Cricetinae , Cricetulus , Humans , In Vitro Techniques , Microsomes, Liver/metabolism , Radioligand Assay , Rats , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred α(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; the corresponding distomers are partial agonists. Because in clinical pain management with opioids α(2C)-AR agonists, devoid of the α(2A)-AR-mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing α(2C)-agonism/α(2A)-antagonism, have been studied in vivo. The data suggest that partial α(2C)-activation is compatible with effective enhancement of morphine analgesia and reduction both of morphine tolerance acquisition and morphine dependence acquisition and expression. On the contrary, full α(2C)-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(+)-4 has been found to be very unusual.
Subject(s)
Adrenergic alpha-2 Receptor Agonists/chemical synthesis , Adrenergic alpha-2 Receptor Antagonists/chemical synthesis , Allyl Compounds/chemical synthesis , Analgesics/chemical synthesis , Imidazolines/chemical synthesis , Morphine Dependence/prevention & control , Morphine/pharmacology , Adrenergic alpha-2 Receptor Agonists/chemistry , Adrenergic alpha-2 Receptor Agonists/pharmacology , Adrenergic alpha-2 Receptor Antagonists/chemistry , Adrenergic alpha-2 Receptor Antagonists/pharmacology , Allyl Compounds/chemistry , Allyl Compounds/pharmacology , Analgesics/chemistry , Analgesics/pharmacology , Animals , CHO Cells , Clonidine/pharmacology , Cricetinae , Cricetulus , Drug Partial Agonism , Drug Tolerance , Humans , Imidazolines/chemistry , Imidazolines/pharmacology , Male , Mice , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
Subject(s)
Hexanes/chemistry , Hexanes/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Cell Membrane/drug effects , Cell Membrane/metabolism , Computer Simulation , Drug Design , Guinea Pigs , Humans , Male , Models, Animal , Models, Chemical , Molecular Structure , Receptors, Dopamine D3/biosynthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
Subject(s)
Azabicyclo Compounds/pharmacology , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacokinetics , Binding, Competitive , Biogenic Monoamines/metabolism , Biological Availability , Biological Transport/drug effects , Cell Line , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Humans , Male , Mice , Microdialysis , Microsomes, Liver/metabolism , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Prefrontal Cortex/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.