874449-07-7

Upstream product

• 110-91-8 morpholine 
• 948883-07-6 5-bromo-N-(4-bromophenyl)pentanamide 
• 4509-90-4 5-bromovaleroyl chloride 
• 2067-33-6 5-bromopentanoic acid 
• 106-40-1 4-bromo-aniline 

Downstream Products

• 1621514-30-4 4-(4-(1-(4-(pyridin-3-yl)phenyl)-1H-tetrazol-5-yl)butyl)morpholine 

Relevant academic research and scientific papers

Structure-activity relationship studies of SEN12333 analogues: Determination of the optimal requirements for binding affinities at α7 nAChRs through incorporation of known structural motifs

Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described α7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the α7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8).

ANTIPRURITIC AGENT

An antipruritic which exerts an antipruritic effect based on a novel action mechanism and is effective for pruritus. The antipruritic contains as an effective ingredient a compound which activates a central type nicotinic acetylcholine receptor.

Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333

Several lines of experimental evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.

Consequences of linker length alteration of the α7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333

A series of ligands based on SEN12333, containing either contracted or elongated alkyl chains, were synthesized and evaluated in molecular docking studies against a homology model of the α7 nicotinic acetylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the exception of the analog containing a 5 methylene unit spacer. However, in vitro competition binding assays revealed that the ligands possessed dissimilar binding affinities, with a Ki range of more than an order of magnitude (Ki = 0.50 to >10 μM), and only SEN12333 itself exhibited functional activity at the α7 nAChR.

Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: Identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-Fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1- ylbutyl) Urea (SEN34625/WYE-103914)

Alpha-7 nicotinic acetylcholine receptor (α7 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 α7 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 α7 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.

SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist

Alpha 7 nicotinic acetylcholine receptor (α7 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 α7 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.

MODULATORS OF ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTORS AND THERAPEUTIC USES THEREOF

The present invention relates to compounds with α7 nAChR agonistic activity, processes for their preparation, pharmaceutical compositions containing the same and the use thereof for the treatment of neurological, psychiatric, cognitive, immunological and inflammatory disorders.