Simon N. Haydar

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

The α7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimers disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of α7 nAChR. SEN12333 shows high affinity for the rat α7 receptor expressed in GH4C1 cells (Ki = 260 nM) and acts as full agonist in functional Ca2+ flux studies (EC50 = 1.6 μM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC50 = 12 μM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at α3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the α7-selective antagonist methyllycaconitine, indicating that it is mediated by α7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel α7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of α7 agonists for treatment of neurodegenerative and cognitive disorders.

Neuronal Nicotinic Acetylcholine Receptors - Targets for the Development of Drugs to Treat Cognitive Impairment Associated with Schizophrenia and Alzheimers Disease

Nicotinic acetylcholine receptors (nAChR) have been strongly implicated as therapeutic targets for treating cognitive deficits in disorders such as schizophrenia and Alzheimers 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 Alzheimers 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.

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

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 Alzheimers 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 Alzheimers 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.

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 (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 Alzheimers 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.

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)

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 Alzheimers 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).

5-Cyclic Amine-3-arylsulfonylindazoles as Novel 5-HT6 Receptor Antagonists

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.

Chapter 3 Small-Molecule Protein–Protein Interaction Inhibitors as Therapeutic Agents for Neurodegenerative Diseases: Recent Progress and Future Directions

Publisher Summary This chapter highlights the recent progress in the development of small-molecule protein–protein interaction inhibitors that have applications in expanding the mechanistic understanding of neurodegenerative diseases, which can potentially lead to the development of rational therapeutics. Substantial genetic and physiological evidence suggest that the A β plays a central role in Alzheimers disease (AD) pathogenesis. A β is a 39-to 42-aminoacid peptide derived from the proteolytic processing of the amyloid precursor protein (APP) by secretases. Gradual changes in the steady-state levels of A β in the brain are thought to initiate the amyloid cascade. The chapter makes two general assumptions regarding the inhibition mechanism of amyloid protein fibril formation by small molecules: (1) specific structural conformation is necessary for β -sheet interaction and stabilization of the inhibition-protein complex and (2) aromatic interaction between the inhibitor molecule and the aromatic residues in the amyloidogenic sequence, potential “hotspots,” may direct the inhibitor to the amyloidogenic core blocking the protein–protein interaction. These assumptions are highly relevant for future design of small-molecule inhibitors as therapeutic agents for the treatment of amyloid-associated diseases.

N-[5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): a medicinal chemistry effort toward an α7 nicotinic acetylcholine receptor agonist preclinical candidate.

α7 Nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimers 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.

1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines are 5-HT6 receptor ligands

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.

SYNTHESIS OF NOVEL 4-FLUORO-2H-PYRAZOL-3-YLAMINES

A new and efficient synthesis for the preparation of novel 4-fluoro-2H-pyrazol-3-ylamines is described. It involves the reaction of an acyl chloride with fluoroacetonitrile and sequential ring closure of the α-fluoro-β-ketonitrile with hydrazine. Utilizing this synthetic protocol, we have synthesized a variety of 4-fluoro-2H-pyrazol-3-ylamines with different steric and electronic demands.