ABSTRACT
Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-Aß peptide antibodies and secretase inhibitors. Most anti-Aß antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aß. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aß antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aß and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aß, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.
Subject(s)
Alzheimer Disease/pathology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Antibodies, Monoclonal/administration & dosage , Aspartic Acid Endopeptidases/antagonists & inhibitors , Brain/drug effects , Enzyme Inhibitors/administration & dosage , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized , Brain/pathology , Disease Models, Animal , Drug Therapy, Combination , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plaque, Amyloid/pathologyABSTRACT
A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment.
Subject(s)
Amides/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Alzheimer Disease/drug therapy , Amides/metabolism , Amides/therapeutic use , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Humans , Molecular Docking Simulation , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Protein Binding , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aß40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aß40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Animals , Brain Chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Female , Fluorine/chemistry , Humans , Indicators and Reagents , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Molecular , Oxazines/chemical synthesis , Oxazines/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects of GPCR drug discovery in the pharmaceutical industry. Applications of pharmacophore similarity analysis of these 1D LPVs include definition of receptor subfamilies, prediction of species differences within subfamilies in regard to in vitro pharmacology and identification of nearest neighbors for GPCRs of interest to generate starting points for GPCR lead identification programs. These aspects of GPCR research are exemplified in the field of melanopsins, trace amine-associated receptors and somatostatin receptor subtype 5. In addition, it is demonstrated how 3D pharmacophore models of the LPVs can support the prediction of amino acids involved in ligand recognition, the understanding of mutational data in a 3D context and the elucidation of binding modes for GPCR ligands and their evaluation. Furthermore, guidance through 3D receptor pharmacophore modeling for the synthesis of subtype-specific GPCR ligands will be reported. Illustrative examples are taken from the GPCR family class C, metabotropic glutamate receptors 1 and 5 and sweet taste receptors, and from the GPCR class A, e.g. nicotinic acid and 5-hydroxytryptamine 5A receptor.
Subject(s)
Drug Discovery/methods , Receptors, G-Protein-Coupled/chemistry , Amino Acid Sequence , Binding Sites , Humans , Ligands , Models, Molecular , Molecular Sequence Data , Protein Conformation , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolismABSTRACT
Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.
Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Animals , Cell Membrane Permeability , Drug Discovery , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , Glycine Plasma Membrane Transport Proteins/analysis , Humans , Isoindoles/chemistry , Isoindoles/pharmacokinetics , Isoindoles/pharmacology , Mice , Rats , Solubility , Structure-Activity RelationshipABSTRACT
Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.
Subject(s)
Niacin/metabolism , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , Receptors, Nicotinic/metabolism , Animals , Microsomes, Liver/metabolism , Pyrimidinones/administration & dosage , Pyrimidinones/metabolism , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Piperazines/chemical synthesis , Psychotropic Drugs/chemical synthesis , Schizophrenia/drug therapy , Sulfones/chemical synthesis , Animals , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Macaca fascicularis , Male , Mice , Microdialysis , Motor Activity/drug effects , Patch-Clamp Techniques , Piperazines/pharmacokinetics , Piperazines/pharmacology , Psychotropic Drugs/pharmacokinetics , Psychotropic Drugs/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Drug Design , Hypoglycemic Agents/chemical synthesis , Quinolizines/chemical synthesis , Animals , Clinical Trials, Phase II as Topic , Crystallography, X-Ray , Delayed-Action Preparations , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dogs , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Macaca fascicularis , Mice , Quinolizines/administration & dosage , Quinolizines/therapeutic use , Rats , Rats, Wistar , Rats, ZuckerABSTRACT
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Quinolizines/chemistry , Animals , Crystallography, X-Ray , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Humans , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Quinolizines/metabolism , Quinolizines/pharmacology , Rats , Rats, ZuckerABSTRACT
Several novel classes of potent and small amide-type inhibitors of glycine transport (GlyT1) were developed through sequential simplification of a benzodiazepinone-lead structure identified from a high-throughput screening. The most potent compounds of these structurally simple classes show low nanomolar inhibition at the GlyT1 target.
Subject(s)
Amides/chemistry , Chemistry, Pharmaceutical/methods , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Glycine Plasma Membrane Transport Proteins/chemistry , Animals , Benzodiazepinones/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Microsomes/chemistry , Models, Chemical , Permeability , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Screening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a structurally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of highly potent compounds displaying excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo efficacy after oral administration.
Subject(s)
Benzoates/chemistry , Benzoates/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Administration, Oral , Brain/drug effects , Combinatorial Chemistry Techniques , Drug Design , Molecular Structure , Structure-Activity RelationshipABSTRACT
The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.
Subject(s)
Anti-Obesity Agents/administration & dosage , Anti-Obesity Agents/pharmacology , Benzodioxoles/administration & dosage , Benzodioxoles/pharmacology , Obesity/drug therapy , Receptor, Cannabinoid, CB1/agonists , Animals , Anti-Obesity Agents/chemistry , Benzodioxoles/chemical synthesis , Benzodioxoles/chemistry , Body Weight/drug effects , Crystallography, X-Ray , Cyclohexanols/antagonists & inhibitors , Cyclohexanols/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Humans , Hypothermia/chemically induced , Ligands , Male , Mice , Microsomes/drug effects , Models, Molecular , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/chemistry , Structure-Activity RelationshipABSTRACT
The desymmetrisation of centrosymmetric molecules by enantioselective carbon-carbon bond formation has been reported for the first time. A bimetallic zinc catalyst developed by Trost was exploited in the desymmetrisation of a centrosymmetric dialdehyde. The approach was successful with a range of ketone nucleophiles and was uniformly highly diastereoselective (>98:<2). The yield and the enantioselectivity of the reaction varied as a function of the ketone used, and the desymmetrised products were obtained in up to 74 % yield and 97 % ee (ee=enantiomeric excess). The desymmetrisation of centrosymmetric molecules by enantioselective carbon-carbon bond formation is an efficient and convergent synthetic approach which is likely to find wide application in synthesis, particularly in the total synthesis of natural products with embedded centrosymmetric fragments.
Subject(s)
Aldehydes/chemistry , Carbon/chemistry , Catalysis , Molecular Conformation , Molecular Structure , Stereoisomerism , Zinc/chemistryABSTRACT
In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Piperidines/chemistry , Protease Inhibitors/chemistry , Adenosine Deaminase/chemistry , Dipeptidyl Peptidase 4/chemistry , Glycoproteins/chemistry , Humans , Piperidines/chemical synthesis , Piperidines/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Protein Conformation , Structure-Activity RelationshipABSTRACT
We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
Subject(s)
GABA-A Receptor Agonists , Phthalazines/chemical synthesis , Triazoles/chemical synthesis , Animals , Binding Sites , Cell Line , Female , Humans , Models, Molecular , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Phthalazines/chemistry , Phthalazines/pharmacology , Protein Subunits/agonists , Protein Subunits/physiology , Radioligand Assay , Receptors, GABA-A/physiology , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacology , Xenopus laevisABSTRACT
2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones are GABAA receptor benzodiazepine binding site ligands with functional selectivity for the alpha3 subtype over the alpha1 subtype. SAR studies to optimise this functional selectivity are described.