33543-62-3Relevant academic research and scientific papers
Structure-Based Design and Discovery of New M2 Receptor Agonists
Fish, Inbar,St??el, Anne,Eitel, Katrin,Valant, Celine,Albold, Sabine,Huebner, Harald,M?ller, Dorothee,Clark, Mary J.,Sunahara, Roger K.,Christopoulos, Arthur,Shoichet, Brian K.,Gmeiner, Peter
supporting information, p. 9239 - 9250 (2017/11/30)
Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
Phenyl ether- and aniline-containing 2-aminoquinolines as potent and selective inhibitors of neuronal nitric oxide synthase
Cinelli, Maris A.,Li, Huiying,Pensa, Anthony V.,Kang, Soosung,Roman, Linda J.,Martásek, Pavel,Poulos, Thomas L.,Silverman, Richard B.
, p. 8694 - 8712 (2015/11/25)
Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
BIARYL DERIVATIVES AS SELECTIVE 17BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 INHIBITORS
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Page/Page column 32, (2012/09/21)
The invention relates to selective, non-steroidal 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) inhibitors of formula (I), their production and use, notably for the treatment and prophylaxis of sex steroid deficient diseases like osteoporosis in men and women.
Biocatalytic enantioselective oxidative C-C coupling by aerobic C-H activation
Schrittwieser, Joerg H.,Resch, Verena,Sattler, Johann H.,Lienhart, Wolf-Dieter,Durchschein, Katharina,Winkler, Andreas,Gruber, Karl,MacHeroux, Peter,Kroutil, Wolfgang
supporting information; experimental part, p. 1068 - 1071 (2011/04/22)
Bridging the gap: The berberine bridge enzyme (BBE) was employed for the first preparative oxidative biocatalytic C-C coupling that leads to a new intramolecular bond. This unique transformation requires O2 as sole stoichiometric oxidant and gives access to novel optically pure (S)-berbine 2 and (R)-1-benzyl-1,2,3,4-tetrahydroisoquinoline 1 alkaloid derivatives by kinetic resolution.
Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids
Schrittwieser, Joerg H.,Resch, Verena,Wallner, Silvia,Lienhart, Wolf-Dieter,Sattler, Johann H.,Resch, Jasmin,MacHeroux, Peter,Kroutil, Wolfgang
experimental part, p. 6703 - 6714 (2011/10/18)
A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.
Synthesis and biological activities of the marine bryozoan alkaloids convolutamines A, C and F, and lutamides A and C
Hashima, Hirofumi,Hayashi, Masahiko,Kamano, Yoshiaki,Sato, Nobuhiro
, p. 1757 - 1766 (2007/10/03)
Synthesis of convolutamines and lutamides, new 2,4,6-tribromo-3-methoxyphenethylamine alkaloids isolated from Floridian marine bryozoan Amathia convoluta, was accomplished by a sequence of reactions starting from 3-hydroxyphenethylamines. Cytotoxities of the synthetic lutamides, convolutamines and their de-O-methyl derivatives were examined using drug-sensitive and -resistant P388 as well as KB cell lines. The bioassay suggests that the 2,4,6-tribromo-3-methoxyphenethylamine is an indispensable unit for detection of the activities. Additionally, a reversal of drug resistance by those alkaloids is recognized. Copyright (C) 2000 Elsevier Science Ltd.
Single electron transfer promoted photocyclization reactions of (aminoalkyl)cyclohexenones. Mechanistic and synthetic features of processes involving the generation and reactions of amine cation and α-amino radicals
Xu, Wei,Zhang, Xiao-Ming,Mariano, Patrick S.
, p. 8863 - 8878 (2007/10/02)
Mechanistic and synthetic aspects of the SET-induced photocyclization reactions of a series of α-, β-, and γ-(aminoethyl)cyclohexenones have been explored. These investigations have provided results that demonstrate that both direct (in MeOH) and SET-sensitized photocyclization reactions of members of this series containing N-(trimethylsilyl)methyl substituents serve as highly efficient methods for preparation of both fused and spiro N-heterobicyclic systems. In addition, as observed earlier, the solvent has been shown to play an important role in governing the chemoselectivity (i.e., amine cation radical desilylation vs deprotonation) of these photocyclizations. Specifically, desilylation is preferred in the polar protic solvent MeOH while deprotonation is favored in the aprotic MeCN. The results also show that the kinetic acidities of amine cation radicals, as judged by photoproduct distributions from reactions conducted in MeCN, are governed in a predictable way by substituents that control the stabilities of the resulting α-amino radical intermediates. Finally, the SET-sensitized reactions of these (aminoethyl)cyclohexenones that proceed via the radical cyclization mechanism are shown to display modest-to-low degrees of stereoselectivity.
