ABSTRACT
Despite several years of research, only a handful of ß-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.
ABSTRACT
In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p Ka of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aß levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF3-group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Administration, Intravenous , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Aspartic Acid Endopeptidases/metabolism , Biological Availability , Cardiovascular Diseases/chemically induced , Chemical and Drug Induced Liver Injury/etiology , Dogs , Drug Evaluation, Preclinical/methods , Drug Stability , ERG1 Potassium Channel/metabolism , Guinea Pigs , Humans , Male , Mice, Inbred Strains , Oxazines/chemistry , Peptide Fragments/cerebrospinal fluid , Protease Inhibitors/administration & dosage , Protease Inhibitors/adverse effects , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The metabotropic glutamate subtypeâ 2 (mGlu2 ) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu2 receptor function with a negative allosteric modulator (NAM) enhances activity-dependent glutamate release, which may be of therapeutic benefit for the treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high-throughput screening (HTS) campaign. The evolution of this hit is described by structure-activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single-digit nanomolar activity in the mGlu2 NAM GTPγS assay. In addition to SAR on inâ vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between inâ vitro potency, free brain concentration, and exâ vivo mGlu2 receptor occupancy. Finally, to obtain improved drug-like compounds, plans for future research are suggested toward increasing free brain concentration while maintaining high inâ vitro potency.
Subject(s)
Pyrazoles/pharmacology , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation/drug effects , Animals , Cell Line , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Permeability/drug effects , Pyrazoles/chemistry , Rats , Structure-Activity RelationshipABSTRACT
As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
Subject(s)
Allosteric Regulation/drug effects , Antipsychotic Agents/therapeutic use , Pyrazines/therapeutic use , Pyrazoles/therapeutic use , Receptor, Metabotropic Glutamate 5/metabolism , Schizophrenia/drug therapy , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , HEK293 Cells , Humans , Male , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats, Sprague-Dawley , Schizophrenia/metabolismABSTRACT
1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aß levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Brain/metabolism , Oxazines/chemical synthesis , Oxazines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Biological Availability , Blood Proteins/metabolism , Blood-Brain Barrier , Cell Line, Tumor , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Dogs , Drug Design , Female , Humans , Male , Mice , Models, Molecular , Oxazines/pharmacokinetics , Protein BindingABSTRACT
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Subject(s)
Antipsychotic Agents/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Imidazoles/chemistry , Pyrimidinones/chemistry , Receptor, Metabotropic Glutamate 5/chemistry , Allosteric Regulation , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacokinetics , Brain/metabolism , Drug Evaluation, Preclinical , Half-Life , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Locomotion/drug effects , Microsomes, Liver/metabolism , Protein Binding , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Receptor, Metabotropic Glutamate 5/metabolism , Structure-Activity RelationshipABSTRACT
We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/therapeutic use , Rats , Rats, Wistar , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo pharmacokinetic properties led to the identification of 27o. With good potency and selectivity for the mGlu2 receptor, 27o affected sleep-wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Indoles/chemical synthesis , Pyridines/chemical synthesis , Receptors, Metabotropic Glutamate/metabolism , Administration, Oral , Allosteric Regulation , Animals , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line , Cricetinae , Cricetulus , Cytochrome P-450 Enzyme Inhibitors , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indoles/pharmacokinetics , Indoles/pharmacology , Ion Channels/antagonists & inhibitors , Male , Mice , Microsomes, Liver/metabolism , Pyridines/pharmacokinetics , Pyridines/pharmacology , Radioligand Assay , Rats , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Sleep/drug effects , Structure-Activity Relationship , Wakefulness/drug effectsABSTRACT
The influence of several modifications on the GPE tripeptide structure upon the binding to GluRs and on their neuroprotective effects has been studied. The results indicated that the prevention of neuronal death showed by GPE and some analogues is not directly related to their affinity at glutamate receptors.
Subject(s)
Neurons/drug effects , Neuroprotective Agents/pharmacology , Oligopeptides/pharmacology , Receptors, Glutamate/drug effects , Receptors, Glutamate/metabolism , Animals , Binding, Competitive , Cell Death/drug effects , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/toxicity , Hippocampus/cytology , Hippocampus/drug effects , Molecular Structure , Neurons/metabolism , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Protein Binding , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A suitable solid-phase approach, based on Fmoc/(t)Bu methodology and on the use of 2-chlorotrityl resin, allowed a rapid and efficient preparation of new GPE analogues. Most of the synthesized tripeptides displayed glutamate receptor binding affinity comparable to that of GPE, but only a few derivatives showed significant neuroprotective activity.
Subject(s)
Peptides/chemical synthesis , Peptides/pharmacology , Amino Acid Sequence , Animals , Cells, Cultured , Hippocampus/drug effects , Molecular Structure , N-Methylaspartate/toxicity , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Peptides/chemistry , Peptides/metabolism , Rats , Receptors, Glutamate/metabolism , Structure-Activity Relationship , Trityl Compounds/chemistryABSTRACT
A series of GPE analogues, including modifications at the Pro and/or Glu residues, was prepared and evaluated for their NMDA binding and neuroprotective effects. Main results suggest that the pyrrolidine ring puckering of the Pro residue plays a key role in the biological responses, while the preference for cis or trans rotamers around the Gly-Pro peptide bond is not important.
Subject(s)
Neuroprotective Agents/chemical synthesis , Oligopeptides/chemical synthesis , Animals , Glutamic Acid/metabolism , Indicators and Reagents , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Rats , Structure-Activity Relationship , Synaptic Membranes/drug effects , Synaptic Membranes/metabolismABSTRACT
[reaction: see text] Thermolysis of enantiopure sulfonyl pyrazolines 4 and 5, easily obtained from (Z)-3-p-tolylsulfinylacrylonitriles (1), afforded sulfonyl cyclopropanes (6, 7) in a completely stereoselective manner in almost quantitative yields. Both cyclopropanes and alkylidenecyclopropanes, containing one or two chiral carbon atoms, one of them being quaternary, were obtained by hydrogenolysis of the C-S bonding and under the conditions reported by Julia, respectively. The highly stereoselective extrusion of nitrogen suggests a concerted mechanism.
