Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

“…An example of the application of fluorination patterning to conformational control is provided by a detailed analysis of the solid state and solution conformations of a series of trifluorinated 1,3-diphenylpropane derivatives. 80 Uniquely, the all-anti isomer 119 was found to adopt a conformation that placed the two aryl rings in a topography that mimicked those of the preferred conformation calculated for 2-benzyl-2,3-dihydrobenzofuran (120). This provides an interesting example of how isosterism at the level of atom replacements (F for H) can translate into potential higher order bioisosteric relationships.…”

“…119b The introduction of a fluorine atom at the bridgehead position of the quinuclidine-based α7-N-acetylcholine receptor inhibitor 263 afforded 264, a compound with a 2.5 unit lower pK a value that effectively addressed the Caco-2 efflux problem associated with the more basic parent compound. 120 Unfortunately, this structural modification also resulted in a significant erosion in receptor recognition.…”

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

“…The amine fragment and the lipophilic aryl group have been demonstrated by Mullen et al to influence the affinity and the selectivity of ligands for the α7 receptor. A variety of functional groups (carbamates, − azaheterocyclic ethers, − and amides − ) have been employed as the central hydrogen bond acceptor (Figure ). The lipophilic pocket in the α7 receptor seems to accommodate significant structural changes.…”

“…Spirooxazolidinone-quinuclidine α7 nAChR agonists utilizing a carbamate as the hydrogen-bond acceptor have been described. These feature both a heteroatom substituent on the carbon β to the quinuclidine nitrogen, which may modulate quinuclidine basicity, and a rigid framework, which is believed to project a group into a hydrophobic pocket. ,− Compound 3 (AR-R17779) exhibits submicromolar binding potency for α7 nAChR ( K i = 92 nM) with very good selectivity versus the 5-HT 3A receptor (inhibition = 2.5% at 10 μM) and acts as a highly efficacious agonist displaying 96% maximal efficacy at rat α7 receptors . Additionally, spirooxazolidinone 4 was shown to be a partial agonist at the α7 receptor ( K i = 3 nM) with similar potency as an antagonist at the 5-HT 3A receptor ( K i = 10 nM) …”

Palladium-Catalyzed Three-Component Reaction: A Novel Method for the Synthesis of N-Acyl Propiolamides

“…Propiolamides are a highly versatile class of intermediates for the synthesis of heterocycles and biologically relevant molecules . To date, extensive studies have generated a number of approaches for the synthesis of propiolamides, as follows: (a) Pd/Cu-catalyzed cross-coupling reaction of alkynes with carbamoyl chlorides; (b) aminocarbonylation of alkynes or arylpropiolic acid with amines and CO gas; (c) cross dehydrogenative coupling of terminal alkynes or alkynyl acid with formamides; (d) aminocarbonylation of alkynes or bromoalkynes with amines using metal carbonyls as the carbonyl source .…”