ABSTRACT
Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.
Subject(s)
Cerebellum/metabolism , Chlorobenzenes/pharmacology , D-Amino-Acid Oxidase/antagonists & inhibitors , D-Amino-Acid Oxidase/metabolism , Enzyme Inhibitors/pharmacology , Pyridazines/pharmacology , Serine/metabolism , Sodium Benzoate/pharmacology , Administration, Oral , Animals , Biomarkers/metabolism , Chlorobenzenes/administration & dosage , Chlorobenzenes/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Male , Mice , Mice, Inbred C57BL , Pyridazines/administration & dosage , Pyridazines/chemistry , Sodium Benzoate/administration & dosage , Sodium Benzoate/chemistryABSTRACT
Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/pharmacokinetics , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/chemistry , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Pyridines/pharmacokinetics , Triazoles/pharmacokineticsABSTRACT
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Subject(s)
Amides/pharmacology , Purinergic P2 Receptor Antagonists/pharmacology , Pyrrolidonecarboxylic Acid/chemistry , Receptors, Purinergic P2X7/drug effects , Amides/chemistry , Drug Discovery , Models, Molecular , Purinergic P2 Receptor Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.
Subject(s)
Analgesics/chemistry , Calcium Channel Blockers/chemistry , Calcium Channels/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Pyridazines/chemistry , Pyridines/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Analgesics/chemical synthesis , Analgesics/therapeutic use , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/therapeutic use , Calcium Channels/metabolism , Calcium Channels, L-Type , Ligands , Pyrazoles/chemical synthesis , Pyridazines/chemical synthesis , Pyridazines/therapeutic use , Pyridines/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.
Subject(s)
Acetamides/chemistry , Anti-Infective Agents/chemical synthesis , Purinergic P2 Receptor Antagonists , Pyrazoles/chemical synthesis , Acetamides/chemical synthesis , Acetamides/pharmacokinetics , Administration, Oral , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacokinetics , High-Throughput Screening Assays , Humans , Injections, Intravenous , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X7 , Structure-Activity RelationshipABSTRACT
A novel series of oxadiazole EP1 receptor antagonists was identified by replacing the amide of a known glycine sulfonamide derivative with a 1,3,4-oxadiazole. Optimization of the substitution patterns on the three aromatic rings led to the identification of high affinity EP1 receptor antagonists. The derivative with highest affinity displayed a binding IC50 of 2.5 nM (pIC50 8.6).
Subject(s)
Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Models, Molecular , Molecular Structure , Protein Binding , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.
Subject(s)
Indenes/chemical synthesis , Piperazines/chemical synthesis , Receptors, Oxytocin/antagonists & inhibitors , Administration, Oral , Animals , Antidiuretic Hormone Receptor Antagonists , Binding, Competitive , Biological Availability , CHO Cells , Calcium Signaling/drug effects , Cricetinae , Cricetulus , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Oxytocin/pharmacology , Piperazines/pharmacokinetics , Piperazines/pharmacology , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity Relationship , Uterine Contraction/drug effectsSubject(s)
Obstetric Labor, Premature/drug therapy , Oxytocin/antagonists & inhibitors , Oxytocin/metabolism , Animals , Female , Humans , Obstetric Labor, Premature/epidemiology , Oxytocin/chemistry , Peptides/chemistry , Peptides/pharmacology , Pregnancy , Structure-Activity Relationship , Uterus/anatomy & histology , Uterus/drug effectsABSTRACT
A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).
Subject(s)
Piperazines/chemical synthesis , Receptors, Oxytocin/antagonists & inhibitors , Administration, Oral , Animals , Antidiuretic Hormone Receptor Antagonists , Biological Availability , Crystallography, X-Ray , Dogs , Humans , Molecular Structure , Piperazines/pharmacokinetics , Piperazines/pharmacology , Radioligand Assay , Rats , Receptors, Oxytocin/chemistry , Serum Albumin/chemistry , Stereoisomerism , Structure-Activity Relationship , Uterine Contraction/drug effects , Vasotocin/analogs & derivatives , Vasotocin/pharmacologyABSTRACT
This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the determination of the stereochemistry of the most potent compounds.
Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptors, Oxytocin/antagonists & inhibitors , Humans , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Studies to discover novel, potent and selective oxytocin antagonists are reported. Combinatorial libraries designed to find novel replacements of fragments of oxytocin antagonist L-371,257, identified pyrimidine, thiazole, indole and benzofuran as potential alternatives to the benzoic acid moiety of L-371,257. Additional investigations identified indole and benzofuran derivatives with potent oxytocin antagonist activity.
Subject(s)
Benzofurans/chemical synthesis , Indoles/chemical synthesis , Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/antagonists & inhibitors , Animals , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , Biological Availability , Dogs , Drug Design , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/pharmacology , Kinetics , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described.