ABSTRACT
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
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
Subject(s)
Indazoles/chemical synthesis , Receptors, AMPA/physiology , Allosteric Regulation , Animals , Calcium/metabolism , Crystallography, X-Ray , Dogs , High-Throughput Screening Assays , Humans , In Vitro Techniques , Indazoles/pharmacokinetics , Indazoles/pharmacology , Ligands , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Patch-Clamp Techniques , Protein Multimerization , Rats , Rats, Sprague-Dawley , Receptors, AMPA/chemistry , Recombinant Proteins/chemistry , Solubility , Structure-Activity Relationship , Swine , Swine, MiniatureABSTRACT
A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor.
Subject(s)
Furans/pharmacology , Pyrrolidines/pharmacology , Receptors, AMPA/drug effects , Central Nervous System/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , Furans/chemistry , Humans , Protein Isoforms , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Structure-Activity Relationship , SulfonamidesABSTRACT
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Subject(s)
Indenes/chemical synthesis , Pyridines/chemical synthesis , Receptors, AMPA/physiology , Sulfonamides/chemical synthesis , Administration, Oral , Allosteric Regulation , Animals , Biological Availability , Blood Proteins/metabolism , Blood-Brain Barrier/metabolism , Callithrix , Cell Line , Crystallography, X-Ray , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Protein Binding , Protein Structure, Tertiary , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Subject(s)
Quinolines/pharmacology , Receptors, Serotonin, 5-HT1/drug effects , Administration, Oral , Animals , Biological Availability , Ligands , Quinolines/administration & dosage , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.
Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Blood-Brain Barrier/metabolism , Cerebral Cortex/metabolism , Humans , In Vitro Techniques , Piperazines/pharmacokinetics , Piperazines/pharmacology , Quinolines/pharmacokinetics , Quinolines/pharmacology , Radioligand Assay , Rats , Recombinant Proteins/pharmacology , Structure-Activity RelationshipABSTRACT
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Agents/metabolism , Administration, Oral , Biological Availability , Ligands , Serotonin Agents/pharmacokineticsABSTRACT
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
Subject(s)
Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Callithrix , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Guinea Pigs , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Piperazines/pharmacology , Pyridines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1B/drug effects , Receptor, Serotonin, 5-HT1D/drug effects , Synaptosomes/drug effectsABSTRACT
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Subject(s)
Amides/chemistry , Amides/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Brain/drug effects , Brain/metabolism , Cattle , Computational Biology , Humans , Ligands , Models, Molecular , Molecular Structure , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Sulfur/chemistryABSTRACT
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
Subject(s)
Amides/pharmacology , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Anilides/chemistry , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Humans , Molecular Structure , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
Subject(s)
Benzoxazines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Benzoxazines/pharmacology , Biological Availability , Brain/metabolism , Cell Line , Drug Stability , Humans , Radioligand Assay , Rats , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Synaptosomes/metabolismABSTRACT
At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.