- Systematic Investigation of the Scope of Transannular C-H Heteroarylation of Cyclic Secondary Amines for Synthetic Application in Medicinal Chemistry
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Transannular C-H heteroarylation of amines provides rapid access to complex scaffolds that are otherwise difficult to synthesize. Wide adaptation of this emerging reaction for medicinal chemistry requires a broad understanding of substrate scope and more robust experimental conditions. In this article, we report a new ligand to promote the transannular reaction of a range of fused- and bridged-bicyclic secondary amines with a broad set of heteroarenes. The method was also successfully applied to the arylation of one spiro-bicyclic amine, a class of substrates that has not been studied in the context of transannular C-H activation reactions. The broad application of this transannular C-H heteroarylation methodology is currently hampered by the difficulty of removing the directing group. The development of a new directing group that is easier to remove will expand the utility of this reaction.
- Li, Zhe,Dechantsreiter, Michael,Dandapani, Sivaraman
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p. 6747 - 6760
(2020/07/14)
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- Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus
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Amantadine has been used for decades as an inhibitor of the influenza A virus M2 protein (AM2) in the prophylaxis and treatment of influenza A infections, but its clinical use has been limited by its central nervous system (CNS) side effects as well as emerging drug-resistant strains of the virus. With the goal of searching for new classes of M2 inhibitors, a structure-activity relation study based on 2-[3-azaspiro(5,5)undecanol]-2-midazoline (BL-1743) was initiated. The first generation BL-1743 series of compounds has been synthesized and tested by two-electrode voltage-clamp (TEV) assays. The most active compound from this library, 3-azaspiro[5,5]undecane hydrochloride (9), showed an IC50 as low as0.92 ± 0.11 μM against AM2, more than an order of magnitude m ore potent than amantadine (IC50 = 16 μM). 15N and 13C solid-state NMR was employed to determine the effect of compound 9 on the structure and dynamics of the transmembrane domain of AM2 (AM2-TM) in phospholipid bilayers. Compared to amantadine, spiro-piperidine 9 (1) induces a more homogeneous conformation of the peptide,(2) reduces the dynamic disorder of the G34-I35 backbone near the water -filled central cavity of the helical bundle, and (3) influences the dynamics and magnetic environment of more residues within the transmembranehelices. These data suggest that spiro-piperidine 9 binds more extensiv ely with the AM2 channel, thus leading to stronger inhibitory potency.
- Wang, Jun,Cady, Sarah D.,Balannik, Victoria,Pinto, Lawrence H.,DeGrado, William F.,Hong, Mei
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experimental part
p. 8066 - 8076
(2009/12/03)
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- PYRAZOLONE COMPOUNDS AS METABOTROPIC GLUTAMATE RECEPTOR AGONISTS FOR THE TREATMENT OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS
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Compounds of Formula (I), wherein R1, R2, R3, R4, R5, R6, X, and n are as defined for Formula (I) in the description, processes for the preparation of the compounds and new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and the use of the compounds in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction.
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Page/Page column 298; 299
(2008/06/13)
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