Design and Synthesis of a New Series of 4-Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure–Activity Relationship

Abstract

The design and synthesis of a series of quinuclidine-containing spirooxazolidines ("spiroimidates") and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'oxazol]-2'-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.

Development of 4-Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes] as α7 Nicotinic Receptor Agonists

“…The S-enantiomer 28 of spiroimidate 21 was prepared and exhibited only a slight loss in α7 nAChR potency and 5-HT 3A selectivity. 18 Target potency dropped considerably when the imidate heteroatoms were exchanged (compound 29). Homologation of the imidate core provided spirocycle 30, which was considerably weaker and failed to offer any improvement over lead spiroimidate 21.…”

“…16,17 In our previous disclosure, we described a novel series of quinuclidinecontaining spirocyclic α7 nAChR partial agonists 1 built on similar principles (Figure 1). 18 In this chemotype, the quinuclidine functioned as the rigid amine, and the spiroimidate provided a centralized hydrogen-bond acceptor. Importantly, this spiroimidate series 1 provided partial agonists, which are expected to mitigate receptor desensitization associated with full agonism.…”

“…Outside of preliminary work focused on establishing the minimum pharmacophore, our previous efforts were largely confined to unsubstituted 6,6-fused biaryls. 18 In this study we prepared 6,5-fused systems with varying substitution patterns to further probe the hypothesized lipophilic pocket of the α7 nAChR. New spiroimidates were readily synthesized in enantiopure form using an established route (Scheme 1).…”

Synthesis of Isoquinolines through IrIII‐Catalyzed C–H Activation/Annulation from Benzimidates with Hydroxylisopropylalkynes

“…Isoquinolines, like some other heterocyclic skeletons widely exist in countless synthetic compounds that display various biological activity, including analgesic, antitumor, anti‐inflammatory, and antipsychotic activity As a result, many efforts have been made to achieve an efficient synthesis of these skeletons. C–H activation/annulation is a topic that currently attracts significant interest.…”

BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia

“…32−34 We identified BMS-902483 (1a) as an early example of a potent α7 nACh receptor partial agonist ( Figure 2). 32 This compound bound with high potency to native rat and recombinant human α7 nAChRs and demonstrated agonist activity in a Ca 2+ fluorescence assay (FLIPR). In whole cell voltage clamp electrophysiology experiments, 1a showed a potent, partial agonist profile (data summarized in Table 1).…”