Discovery of fused azetidines as novel selective α4β2 neuronal nicotinic receptor (NNR) agonists

Ji, Jianguo; Bunnelle, William H.; Li, Tao; Pace, Jennifer M.; Schrimpf, Michael R.; Sippy, Kevin B.; Anderson, David J.; Meyer, Michael D.

doi:10.1351/pac200577122041

Cited by 15 publications

(5 citation statements)

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“…The efficient synthesis of this compound used a palladium-catalysed coupling for the final step connecting 3-bromo-5-cyanopyridine ( 9 ) with the protected (1 R ,5 S )-3,6-diazabicyclo[3.2.0]heptane 10 . The use of Cs 2 CO 3 instead of the conventional base t -BuONa increased the yield of 11 from 47% to 73% ( Scheme 3 ) [ 52 ]. The enantioselective synthesis of A-366833 allowed large-scale preparation required for preclinical investigations.…”

Section: Reviewmentioning

confidence: 99%

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

Fischer¹,

Koenig²

2011

Beilstein J. Org. Chem.

210

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SummaryN-Arylated aliphatic and aromatic amines are important substituents in many biologically active compounds. In the last few years, transition-metal-mediated N-aryl bond formation has become a standard procedure for the introduction of amines into aromatic systems. While N-arylation of simple aromatic halides by simple amines works with many of the described methods in high yield, the reactions may require detailed optimization if applied to the synthesis of complex molecules with additional functional groups, such as natural products or drugs. We discuss and compare in this review the three main N-arylation methods in their application to the synthesis of biologically active compounds: Palladium-catalysed Buchwald–Hartwig-type reactions, copper-mediated Ullmann-type and Chan–Lam-type N-arylation reactions. The discussed examples show that palladium-catalysed reactions are favoured for large-scale applications and tolerate sterically demanding substituents on the coupling partners better than Chan–Lam reactions. Chan–Lam N-arylations are particularly mild and do not require additional ligands, which facilitates the work-up. However, reaction times can be very long. Ullmann- and Buchwald–Hartwig-type methods have been used in intramolecular reactions, giving access to complex ring structures. All three N-arylation methods have specific advantages and disadvantages that should be considered when selecting the reaction conditions for a desired C–N bond formation in the course of a total synthesis or drug synthesis.

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Section: Reviewmentioning

confidence: 99%

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

Fischer¹,

Koenig²

2011

Beilstein J. Org. Chem.

210

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“…However, its development was discontinued after phase II because of adverse side effects in initial clinical trials. [255] Two other compounds, ABT-202 (78) and A-366833 (79) [256] are reported to be in phase I for pain treatment, [255] but details on their pharmacology are not available. Two compounds of the SIBIA group are in development for Parkinson disease (SIB-1508Y, 80) and cognition dysfunction (SIB-1553A, 81), respectively ( Figure 11).…”

Section: Compounds In Developmentmentioning

confidence: 99%

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

et al. 2007

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The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

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“…Natural and bioactive compounds such as vitamin B12 [4], nicotine [5], nornicotine [6], hygrine, hygroline, and cuscohygrine [7] are some of the pyrrolidine alkaloids [4][5][6] (Figure 3). Many compounds containing pyrrolidine ring have different bioactive properties such as antitumor [8], analgesic [9], anesthetic [10], antifungal [11], antibacterial [12], insecticidal [13], anthelmintic [13], antileukemic [14], anticonvulsant [14], and antidepressant effects [15]. Some pyrrolidine derivatives have also been shown to have an enzyme inhibitory effect [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

"Synthesis of Bicyclic Pyrrolidine Derivatives and their Photoluminescent Properties"

Kishalı

2023

BJSTR

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A new and convenient synthesis for pyrrolidine derivatives has been developed starting from 3a,4,7,7atetrahydroisobenzofuran-1,3-dione. 3a,4,7,7a-tetrahydroisobenzo furan-1,3-dione was reacted with amines to give N-ethyl and N-phenyl isoindole derivatives. These amine compounds are reduced to bicyclic pyrrolidine derivatives with LiAlH4. Pyrrolidine derivatives absorption and fluorescence spectra were recorded with different concentrations and solubility systems. One of the derivatives exhibited the highest fluorescence quantum efficiency in ethanol and the other in DCM.

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Discovery of fused azetidines as novel selective α4β2 neuronal nicotinic receptor (NNR) agonists

Cited by 15 publications

References 0 publications

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

"Synthesis of Bicyclic Pyrrolidine Derivatives and their Photoluminescent Properties"

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