ABSTRACT
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 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
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
Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.
Subject(s)
Indazoles/metabolism , Receptors, Serotonin/metabolism , Serotonin Antagonists/metabolism , Sulfones/metabolism , Animals , Binding, Competitive , Brain/metabolism , Exploratory Behavior/drug effects , Habituation, Psychophysiologic/drug effects , Humans , Indazoles/chemistry , Indazoles/pharmacology , Models, Chemical , Molecular Structure , Rats , Receptor, Serotonin, 5-HT2B/chemistry , Receptor, Serotonin, 5-HT2B/metabolism , Receptors, Serotonin/chemistry , Recognition, Psychology/drug effects , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
Nicotinic acetylcholine receptors (nAChR) have been strongly implicated as therapeutic targets for treating cognitive deficits in disorders such as schizophrenia and Alzheimer's disease (AD). In particular alpha7 and alpha4beta2 subtype-selective nAChR agonists and partial agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Further development of positive allosteric modulators and antagonists were also recently reported in the literature. In this review we will cover recent developments focused on the above mentioned nAChR subtypes, starting from the most advanced clinical candidate followed by an overview of literature compounds where potency, selectivity, central nervous system access, pharmacological activity and pharmacokinetic properties are disclosed.
Subject(s)
Alzheimer Disease/drug therapy , Cognition Disorders/complications , Cognition Disorders/drug therapy , Drug Discovery , Nicotinic Antagonists/pharmacology , Receptors, Nicotinic/metabolism , Schizophrenia/drug therapy , Alzheimer Disease/complications , Alzheimer Disease/metabolism , Cognition Disorders/metabolism , Nicotinic Antagonists/therapeutic use , Schizophrenia/complications , Schizophrenia/metabolism , Structure-Activity RelationshipABSTRACT
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Subject(s)
Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , HeLa Cells , Humans , Ligands , Pyridines/chemistry , Pyrroles/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistryABSTRACT
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.
