Discovery of a Novel Alpha-7 Nicotinic Acetylcholine Receptor Agonist Series and Characterization of the Potent, Selective, and Orally Efficacious Agonist 5-(4-Acetyl[1,4]diazepan-1-yl)pentanoic Acid [5-(4-Methoxyphenyl)-1H-pyrazol-3-yl] Amide (SEN15924, WAY-361789)

Abstract

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).

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).…”

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

“…Hybrid compound 47 explores the direct transposition of the biaryl moiety of lead compound 9 onto SEN12333 (8). Compounds 48e50 involve the incorporation of a phenyl-substituted-pyrazole ring as the biaryl motif of SEN12333 (8), in order to potentially enhance the hydrogen bonding capacity of the biaryl system within the a 7 active site [44].…”

“…3 [44]. Series 1 is representative of SEN12333 (8), whilst Series 2 described replacement of the amide moiety with urea functionality [45].…”

“…Series 2 generally exhibits enhanced potency at a7 nAChRs as compared to Series 1, however, it also demonstrated low selectivity particularly against the homologous a3 receptor, unfavourable hERG activity and substantial cytochrome P450 inhibition [45]. The development of Series 3 resulted in compounds with a good level of potency, improved selectivity, an optimal hERG profile and no cytochrome P450 inhibition [44]. Series 3 retains two hydrogen bond donors and therefore encompasses the possibility of additional interactions when compared to Series 1 and 2 [44].…”

“…The development of Series 3 resulted in compounds with a good level of potency, improved selectivity, an optimal hERG profile and no cytochrome P450 inhibition [44]. Series 3 retains two hydrogen bond donors and therefore encompasses the possibility of additional interactions when compared to Series 1 and 2 [44].…”