ABSTRACT
Alpha 7 nicotinic acetylcholine receptor (alpha(7) nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the alpha(7) nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed.
Subject(s)
Morpholines/chemistry , Morpholines/pharmacology , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Alzheimer Disease/drug therapy , Animals , Binding, Competitive , Calcium/metabolism , Cell Line , Cognition/drug effects , Electrophysiology , Humans , Morpholines/pharmacokinetics , Nicotinic Agonists/pharmacokinetics , Pyridines/pharmacokinetics , Rats , Rats, Wistar , Schizophrenia/drug therapy , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A novel approach towards quinone methides stabilization has been achieved by anchoring the reactive o-QM intermediate on solid phase (RTHP). The reactivity and selectivity of supported o-QM towards N and S centered nucleophiles have been explored.
ABSTRACT
α7 nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. As a follow up of our internal medicinal chemistry program we investigated a novel series of α7 nAChR agonists. Starting from molecular docking studies on two series of molecules recently developed in our laboratories, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. Based on our previous SAR knowledge and on predicted drug-like properties, a small library was synthesized in parallel manner, affording compounds with excellent α7 nAChR activity, selectivity and preliminary ADME profile.
Subject(s)
Drug Design , Pyrazoles/pharmacology , Urea/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/agonists , Animals , Cell Membrane Permeability/drug effects , Dogs , Dose-Response Relationship, Drug , Humans , Male , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemical synthesisABSTRACT
Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).
Subject(s)
Azepines/chemical synthesis , Nicotinic Agonists/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Nicotinic/metabolism , Administration, Oral , Animals , Azepines/pharmacokinetics , Azepines/pharmacology , Brain/metabolism , Calcium/metabolism , Catalytic Domain , Cell Line , Cell Membrane Permeability , Cognition/drug effects , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Male , Membrane Potentials/drug effects , Models, Molecular , Nicotinic Agonists/pharmacokinetics , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/chemical synthesis , Nicotinic Antagonists/pharmacokinetics , Nicotinic Antagonists/pharmacology , Patch-Clamp Techniques , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Radioligand Assay , Rats , Rats, Long-Evans , Reflex, Startle/drug effects , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
α7 Nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.
Subject(s)
Brain/drug effects , Cognition/drug effects , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Nicotinic Agonists/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptors, Nicotinic/chemistry , Animals , CHO Cells , Calcium/metabolism , Chemistry, Pharmaceutical , Cricetinae , ERG1 Potassium Channel , Humans , Models, Molecular , Nicotinic Agonists/chemical synthesis , Piperidines/chemical synthesis , Pyrazoles/chemical synthesis , Rats , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
Subject(s)
Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacology , Administration, Oral , Animals , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/pharmacokinetics , Protein Conformation , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats , Receptors, Nicotinic/chemistry , Structure-Activity Relationship , Substrate Specificity , Urea/administration & dosage , Urea/pharmacokinetics , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
The accessibility of various solid supports (TentaGel, PEGA 1900, and beaded controlled pore glasses (CPGs)) to a range of enzymes was investigated. The different beaded materials were loaded with the peptide 4-cyanobenzamide-Gly-Pro-Leu-Gly-Leu-Phe-Ala-Arg-OH and incubated with the enzymes MMP-12 (22 kDa), thermolysin (35 kDa), MMP-13 (42.5 kDa), clostridium collagenase (68 kDa), and NEP (90 kDa). The absence/presence of the cyano stretching frequency was measured by means of confocal Raman microscopy. It was found that none of the investigated enzymes could enter the polymer matrices of TentaGel. PEGA 1900 was compatible only with the two smallest enzymes, while beaded CPG was successful even with NEP (90 kDa), proving its superiority over other materials in terms of bio-compatibility.
Subject(s)
Biocompatible Materials/metabolism , Enzymes, Immobilized/chemistry , Enzymes, Immobilized/metabolism , Biocompatible Materials/chemistry , Collagenases/chemistry , Collagenases/metabolism , Combinatorial Chemistry Techniques , Matrix Metalloproteinase 12 , Matrix Metalloproteinase 13 , Metalloendopeptidases/chemistry , Metalloendopeptidases/metabolism , Molecular Weight , Oligopeptides/chemistry , Spectrum Analysis, Raman , Thermolysin/chemistry , Thermolysin/metabolismABSTRACT
Fluorescence microscopy is a powerful technique for analyzing beads with very low loadings of fluorophores; however, the method is flawed when looking at more highly loaded beads as a result of severe problems with absorption. To probe distributions at higher loading levels, Raman spectroscopy avoids many of these issues. These studies show that there is a uniform distribution of reactive sites throughout the beads but that the spatial distribution of reacted sites depends on the polymer type, with a fine balance between reaction and diffusion rate.