ABSTRACT
We herein report the discovery of a new γ-secretase modulator class with an aminothiazole core starting from a HTS hit (3). Synthesis and SAR of this series are discussed. These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aß) peptide production. Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aß42 peptide is shifted to smaller non-aggregating Aß peptides. Compound 15 reduced brain Aß42 in vivo in APPSwe transgenic mice at 30mg/kg p.o.
Subject(s)
Amyloid Precursor Protein Secretases/drug effects , Thiazoles/pharmacology , Animals , Humans , Mice , Mice, Transgenic , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
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
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
Small molecule mGluR1 enhancers, which are 9H-xanthene-9-carboxylic acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides, have been previously reported. Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides with improved pharmacokinetic properties have been designed and synthesized as useful pharmacological tools for the study of the physiological roles mediated by mGlu1 receptors. The synthesis and the structure-activity relationship of this class of positive allosteric modulators of mGlu1 receptors will be discussed in detail.
Subject(s)
Amides/chemistry , Chemistry, Pharmaceutical/methods , Receptors, Metabotropic Glutamate/chemistry , Administration, Oral , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Electrophysiology/methods , Humans , Models, Chemical , Molecular Structure , Rats , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity RelationshipABSTRACT
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
A novel class of 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. A novel, straightforward and efficient synthetic strategy for the assembly of the target molecules is also presented.
Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Opioid Peptides/chemistry , Peptides/chemistry , G Protein-Coupled Inwardly-Rectifying Potassium Channels/chemistry , Humans , Inhibitory Concentration 50 , Models, Chemical , Protein Isoforms , Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, Opioid/chemistry , Stereoisomerism , X-Rays , NociceptinABSTRACT
A novel class of 4-substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor. These molecules also exhibit superior pharmacological and pharmacokinetic parameters, relative to all GlyT1 inhibitors of the spiropiperidine family, culminating in the identification of 16b with an oral bioavailability of approximately 60%. In addition, a straightforward two-step procedure for the assembly of the target molecules is also presented.
Subject(s)
Glycine Plasma Membrane Transport Proteins/chemistry , Piperidines/pharmacology , Spiro Compounds/pharmacology , Administration, Oral , Animals , Ether-A-Go-Go Potassium Channels/metabolism , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Microsomes , Models, Chemical , Opioid Peptides/chemistry , Piperidines/chemistry , Protein Binding , Protein Isoforms , Spiro Compounds/chemistry , Temperature , NociceptinABSTRACT
A novel class of 4-aryl-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1- ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu-opioid receptor as well as the Nociceptin/Orphanin FQ peptide (NOP) receptor. In particular these novel compounds 4 as well as the 4-substituted-8-(2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one 3 show improved metabolic stability and pharmacokinetic profiles in rodents compared to previous triazaspiropiperidine series 1 and 2. We have also identified within these diazaspiropiperidine series a key relationship between reducing basicity of the piperidine nitrogen and reducing hERG affinity.
Subject(s)
Ether-A-Go-Go Potassium Channels/metabolism , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Opioid Peptides/chemistry , Animals , Chemistry, Pharmaceutical , Drug Design , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Microsomes/metabolism , Models, Chemical , Peptides/chemistry , Protein Isoforms , Receptors, Opioid/chemistry , NociceptinABSTRACT
Small molecule mGluR1 enhancers based on the lead compound (9H-xanthene-9-carbonyl)-carbamic acid butyl ester derived from random-screening hit diphenylacetyl-carbamic acid ethyl ester were designed and synthesized as useful pharmacological tools for the study of the physiological roles mediated by mGlu1 receptors. The synthesis and the structure-activity relationship of this new class of positive allosteric modulators of mGlu1 receptors will be discussed in detail.
Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Oxadiazoles/pharmacology , Receptors, Metabotropic Glutamate/agonists , Tetrazoles/pharmacology , Allosteric Regulation , Animals , Excitatory Amino Acid Agonists/administration & dosage , Excitatory Amino Acid Agonists/chemistry , Excitatory Amino Acid Agonists/pharmacokinetics , Oxadiazoles/administration & dosage , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Rats , Spectrometry, Fluorescence , Tetrazoles/administration & dosage , Tetrazoles/chemistry , Tetrazoles/pharmacokineticsABSTRACT
New orally active non-terpenoic inhibitors of human 2,3-oxidosqualene cyclase (hOSC) are reported. The starting point for the optimization process was a set of compounds derived from a fungicide project, which in addition to showing high affinity for OSC from Candida albicans showed also high affinity for human OSC. Common structural elements of these inhibitors are an amine residue and an electrophilic carbonyl C atom embedded in a benzophenone system, which are at a distance of about 10.7 A. Considering that the keto moiety is in a potentially labile position, modifications of the substitution pattern at the benzophenone as well as annelated heteroaryl systems were explored. Our approach combined testing of the compounds first for increased binding affinity and for increased stability in vitro. Most promising compounds were then evaluated for their efficacy in lowering plasma total cholesterol (TC) and plasma low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic hamsters. In this respect, the most promising compounds are the benzophenone derivative 1.fumarate and the benzo[d]isothiazol 24.fumarate, which lowered TC by 40% and 33%, respectively.