ABSTRACT
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/pharmacokinetics , Dogs , Half-Life , Haplorhini , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Male , Microsomes, Liver/metabolism , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Niacinamide/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Cytochrome P-450 CYP2D6/chemistry , Cytochrome P-450 CYP2D6/metabolism , Drug Evaluation, Preclinical , Half-Life , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Protein Binding , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , 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
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.
Subject(s)
Quinolones/chemistry , Receptors, Serotonin, 5-HT1/drug effects , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Animals , Autoreceptors/antagonists & inhibitors , Autoreceptors/drug effects , Quinolones/pharmacokinetics , Rats , Selective Serotonin Reuptake Inhibitors/pharmacology , Synapses/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
Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Antidepressive Agents/chemical synthesis , Benzoxazines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Callithrix , Cell Line , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme System/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Humans , In Vitro Techniques , Male , Microsomes, Liver/metabolism , Protein Binding , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins/metabolism , Structure-Activity RelationshipABSTRACT
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
The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.
Subject(s)
Brain/drug effects , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Receptors, Dopamine D2/agonists , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Brain/metabolismABSTRACT
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 synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.
Subject(s)
Imidazolidines/chemistry , Positron-Emission Tomography , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Cats , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Ligands , Receptors, Dopamine D3/metabolism , Structure-Activity RelationshipABSTRACT
The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.
Subject(s)
Imidazolidines/chemistry , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Brain/drug effects , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Dopamine D2 Receptor Antagonists , Humans , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Inhibitory Concentration 50 , Ligands , Models, Chemical , Positron-Emission Tomography , Rats , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Structure-Activity Relationship , SwineABSTRACT
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Female , Forelimb/drug effects , Gerbillinae , Humans , Male , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Psychological Tests , Pyridines/chemistry , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Ultrasonics , Vocalization, Animal/drug effectsABSTRACT
In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.
Subject(s)
Computer Simulation , Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Binding Sites , CHO Cells , Cricetinae , Cricetulus , Drug Design , Ligands , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Quantitative Structure-Activity Relationship , StereoisomerismABSTRACT
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Benzazepines/chemistry , Combinatorial Chemistry Techniques , Dopamine Antagonists/chemistry , Drug Design , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.
Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Benzazepines/chemistry , Combinatorial Chemistry Techniques , Dopamine Antagonists/chemistry , Drug Design , Molecular Structure , Rats , Structure-Activity RelationshipSubject(s)
Anxiety/drug therapy , Depression/drug therapy , Drug Design , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anxiety/pathology , Corticotropin-Releasing Hormone/metabolism , Depression/pathology , Models, Chemical , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
Subject(s)
Benzazepines/chemical synthesis , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/chemical synthesis , Acetylcholine/metabolism , Administration, Oral , Alcohol Drinking/prevention & control , Animals , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Brain/blood supply , Brain/metabolism , Cocaine/pharmacology , Conditioning, Operant/drug effects , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/pharmacology , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D3/agonists , Receptors, Histamine H1/metabolism , Structure-Activity Relationship , Tobacco Use Disorder/prevention & control , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.
Subject(s)
Naphthalenes/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Administration, Oral , Humans , Naphthalenes/administration & dosage , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Recombinant Proteins/antagonists & inhibitorsABSTRACT
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.
Subject(s)
Benzazepines/pharmacology , Brain/drug effects , Histamine Antagonists/pharmacology , Niacinamide/analogs & derivatives , Nootropic Agents/pharmacology , Receptors, Histamine H3/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Animals , Benzazepines/metabolism , Benzazepines/pharmacokinetics , Binding, Competitive , Brain/metabolism , Brain/pathology , Cell Line , Dogs , Histamine Agonists/metabolism , Histamine Agonists/pharmacokinetics , Histamine Agonists/pharmacology , Histamine Antagonists/metabolism , Histamine Antagonists/pharmacokinetics , Humans , Male , Maze Learning/drug effects , Mice , Middle Aged , Neurotransmitter Agents/metabolism , Niacinamide/metabolism , Niacinamide/pharmacokinetics , Niacinamide/pharmacology , Nootropic Agents/metabolism , Nootropic Agents/pharmacokinetics , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Histamine H3/analysis , Sus scrofaABSTRACT
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.