ABSTRACT
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dogs , Nicotinic Agonists/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A series of α7 nicotinic acetylcholine receptor full agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Early lead 1 was found to have a limited therapeutic index with respect to its potential for cardiovascular side effects. Further optimisation of this series led to the identification of 22 a potent full agonist showing efficacy at a dose of 0.1mg/kg in the novel object recognition model of cognition enhancement. Comparison of 1 with 22 demonstrated the latter to have an improved oral pharmacokinetic profile and cardiovascular therapeutic index.
Subject(s)
Cognition/drug effects , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/drug effects , Animals , Dose-Response Relationship, Drug , Rabbits , Receptors, Nicotinic/chemistry , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Arginine/chemistry , Ethylamines/chemistry , Protease Inhibitors/chemistry , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Ethylamines/chemical synthesis , Ethylamines/therapeutic use , Protease Inhibitors/chemical synthesis , Protease Inhibitors/therapeutic use , 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
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Thiazines/chemistry , Administration, Oral , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Computer Simulation , Ethylamines/chemical synthesis , Ethylamines/chemistry , Ethylamines/pharmacology , Humans , Mice , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/pharmacokineticsABSTRACT
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemistry , Protease Inhibitors/chemistry , Administration, Oral , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Computer Simulation , Crystallography, X-Ray , Ethylamines/chemical synthesis , Ethylamines/pharmacology , Humans , Mice , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Thiazines/chemistry , Thiazines/pharmacologyABSTRACT
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemistry , Protease Inhibitors/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Biological Availability , Dogs , Ethylamines/chemical synthesis , Ethylamines/pharmacokinetics , Mice , Mice, Knockout , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzothiadiazines/chemical synthesis , Cyclic S-Oxides/chemical synthesis , Ethylamines/chemical synthesis , Administration, Oral , Animals , Benzothiadiazines/pharmacokinetics , Benzothiadiazines/pharmacology , Biological Availability , Cyclic S-Oxides/pharmacokinetics , Cyclic S-Oxides/pharmacology , Dogs , Ethylamines/pharmacokinetics , Ethylamines/pharmacology , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
Subject(s)
Alzheimer Disease/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Ethylamines/chemical synthesis , Ethylamines/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Crystallography, X-Ray , Ethylamines/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
Subject(s)
Alzheimer Disease/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Ethylamines/chemical synthesis , Ethylamines/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Protein Precursor/antagonists & inhibitors , Animals , Asparagine/chemistry , Crystallography, X-Ray , Disease Models, Animal , Ethylamines/chemistry , Fluorine/chemistry , Mice , Molecular Structure , Nanotechnology , Structure-Activity RelationshipABSTRACT
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
