Discovery of 3-(5-Chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a Novel Highly Selective α4β2 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders

Abstract

Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4β2 nAChR selective agonists comprising a series of N-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4β2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (56, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimer's disease.

Identification and pharmacological characterization of 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the α4β2 and α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs)

“…Recent work by Targacept with the development of AZD1446 (3-(5-chloro-2-furoyl)-3,7-diazabicyclo [3.3.0]octane), a highly selective a4b2 nAChR agonist, has shown that bioisoteric replacement of pyridine as the hydrogen bond acceptor (HBA) is a viable strategy for drug discovery in nAChR [20]. The alkaloid epibatidine (1) has long been known as a potent ligand for a4b2 and other nAChRs with adverse effects on CNS responses, respiration, GI and cardiovascular function.…”

Pozanicline for the treatment of attention-deficit/hyperactivity disorder

“…However, it failed to demonstrate improvement in cognition in a large study of stable patients with schizophrenia treated with an atypical antipsychotic [47]. A third a 4 b 2 NNR agonist, AZD1446, improved attention and memory in rodents [48]. Although it was well tolerated in humans, it failed to show improvement in cognitive functioning in subjects with ADHD [49].…”

Nicotinic Acetylcholine Receptor Modulators

“…This was followed up by a more robust randomized, double-blind, placebo-controlled, crossover study of ABT-418 with 236 patients, where the compound demonstrated significant improvement on the primary outcome compared with placebo, as well as in several secondary outcome measures [67]. AZD1446 (7, TC-6683) is a highly selective agonist of central α4β2 and α2β2 neuronal nicotinic receptors [68]. The compound, which is in phase II, has been shown to improve cognition in multiple animal models and has demonstrated potential for treatment of cognitive disorders, including Alzheimer's disease (AD) and schizophrenia.…”