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 range of 3-alkylated five-membered ring derivatives of Gabapentin were synthesized and several were found to have good levels of potency against the alpha2delta calcium subunit of a voltage-gated calcium channel. Two compounds were profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacology , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Calcium Channels/metabolism , Carrageenan/pharmacology , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacology , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , Stereoisomerism , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacologyABSTRACT
A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety.
Subject(s)
Amines/chemistry , Amino Acids/chemical synthesis , Anti-Anxiety Agents/chemical synthesis , Cyclohexanecarboxylic Acids/chemistry , Cyclopentanes/chemical synthesis , gamma-Aminobutyric Acid/chemistry , Amines/chemical synthesis , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Cyclohexanecarboxylic Acids/chemical synthesis , Cyclohexanecarboxylic Acids/pharmacokinetics , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Disease Models, Animal , Gabapentin , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Rats , gamma-Aminobutyric Acid/chemical synthesis , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.
Subject(s)
Amines/chemical synthesis , Amino Acids/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Cyclohexanecarboxylic Acids/chemical synthesis , gamma-Aminobutyric Acid/chemical synthesis , Amines/chemistry , Amines/pharmacokinetics , Amino Acids/chemistry , Amino Acids/pharmacokinetics , Animals , Blood-Brain Barrier/metabolism , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/pharmacokinetics , Gabapentin , Neuralgia/drug therapy , Pain Measurement , Rats , Stereoisomerism , Structure-Activity Relationship , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
The development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed.