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)

Abstract

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.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Complemented by experiments using site-directed mutagenesis and/or sulfhydryl reagents to modify accessibility to the cysteines in the LBD, data further highlighted the role of key amino acid residues that are thought to contribute to the pharmacophore (Papke et al, 2011a). Computer modeling and docking of molecules based on known structures rapidly expanded the number of molecules that demonstrated selectivity for a7 nAChRs, as illustrated in the medicinal chemistry literature Ghiron et al, 2010;Schrimpf et al, 2012;Kombo et al, 2012;Zanaletti et al, 2012). Computer modeling further pointed to the role of fractional hydrophobicity/ hydrophilicity of the LBD and the contribution of the cation-p interaction of the ligand's basic nitrogen atom with tryptophan 149 of the LBD (Kombo and Bencherif, 2013).…”

Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625

“…(Ghiron et al 2010). Treatment with WYE-103914 resulted in significantly greater time spent exploring the novel compared to the familiar object demonstrating enhanced retention of the previous learning experience (Fig.…”

“…WYE-103914, a selective and potent α7 nAChR agonist (Ghiron et al 2010), was found to be active in multiple memory models in the rat and mouse. These models include the pharmacological disruption of memory using the NMDA antagonist MK-801 in the novel object recognition paradigm in rats, and the delay-induced deficit NOR model in rats, as shown in the current study.…”

“…Dose calculations were based on the active moiety. Dose selections for WYE-103914 were initially based on efficacy data reported previously in models of MK-801 disrupted novel object recognition and prepulse inhibition in rats (Ghiron et al 2010). Dose selection of MK-801, APO, RISP, and ARIP were also based on historical internal data in the appropriate assays.…”

“…1; Ghiron et al 2010). WYE-103914 possesses potent and partial agonist activity at α7 nAChR expressed recombinantly (EC 50 = 130 nM, E max =99%), and shows >200-fold selectivity against α4β2 nicotinic acetylcholine and 5-HT 3 serotonergic receptors, as well as several G-protein coupled receptors.…”