ABSTRACT
In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4ß2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.
Subject(s)
Brain/diagnostic imaging , Cognition Disorders/drug therapy , Fluorine Radioisotopes/chemistry , Isotope Labeling , Nicotinic Agonists/pharmacology , Positron-Emission Tomography , Quinuclidines/pharmacology , Triazoles/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/agonists , Animals , Brain/metabolism , Cell Survival/drug effects , Cognition Disorders/metabolism , Dose-Response Relationship, Drug , Ligands , Molecular Structure , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/chemistry , Quinuclidines/chemical synthesis , Quinuclidines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Tumor Cells, Cultured , alpha7 Nicotinic Acetylcholine Receptor/metabolismABSTRACT
We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4ß2 nicotinic receptor (up to 1 µM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported.
Subject(s)
Structure-Activity Relationship , Triazoles/chemistry , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Chemistry Techniques, Synthetic , Click Chemistry , Drug Design , Drug Evaluation, Preclinical/methods , Humans , Inhibitory Concentration 50 , Ligands , Rats , Receptors, Nicotinic/metabolism , Serotonin 5-HT3 Receptor Antagonists/chemistry , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Triazoles/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/agonistsABSTRACT
In this report, we describe the synthesis of a novel library of α7 nAChR ligands based on the modulation of the quinuclidine, quinazoline and tropane moieties. Spirane derivatives were newly synthesized under stereo specific 1,3 dipolar cylcoadditions. Only amide derivatives bonded efficiently to the receptor with Ki measured between 14 and 133 nM. The best fluorinated candidate was selected and radiolabeled. The potent [(18)F]4 PET tracer was evaluated in rats and its brain accumulation quantified.
Subject(s)
Brain/metabolism , Drug Design , Quinazolines/pharmacology , Quinuclidines/pharmacology , Tropanes/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Fluorine Radioisotopes , Ligands , Male , Models, Molecular , Positron-Emission Tomography , Quinazolines/chemistry , Quinuclidines/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Tissue Distribution , Tropanes/chemistryABSTRACT
The pot, atom, and step-economic synthesis of Rosettacin topo-I poison and its derivatives has been achieved using a novel domino N-amidoacylation/aldol-type condensation, followed by decarboxylation of the ester function. The key domino procedure simply involves mixing HOBt ester as new reagent with lactam and NaH together in THF or THF/ DMF. The reaction seems to be general and led to suitable N-heterocyclic products in moderate to good yields.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Topoisomerase I Inhibitors , Acylation , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacologyABSTRACT
Bismuth(III) triflate was found to promote the formation of stable cyclic N-acyliminium species in remarkable catalytic amounts (1 mol %). The alpha-amidoalkylation process seems to be effective in intermolecular and intramolecular manners leading to alpha-substituted lactams and heterocyclic systems containing azacycles, respectively. By comparing our results with those obtained with the classical Lewis acids as catalysts, it was evidenced clearly that the use of bismuth(III) triflate had been efficient for nearly all alpha-acetoxy lactams we used, except for N-acyliminium precursors bearing a sulfur atom. Also, the process seems to be easy, general, and clean, having diastereoselectivity comparable to protocols using classical Lewis acids and resulting in the formation of polyheterocyclic systems in good to excellent yields (64-99% in acetonitrile as solvent).
