- N-skatyltryptamines-dual 5-ht6r/d2r ligands with antipsychotic and procognitive potential
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A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.
- Bojarski, Andrzej J.,Bugno, Ryszard,Cie?lik, Paulina,Duszyńska, Beata,Handzlik, Jadwiga,Hogendorf, Adam S.,Hogendorf, Agata,Kaczorowska, Katarzyna,Kurczab, Rafa?,Latacz, Gniewomir,Lenda, Tomasz,Sata?a, Grzegorz,Staroń, Jakub,Szewczyk, Bernadeta
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- Iridium-Catalyzed Direct Regioselective C4-Amidation of Indoles under Mild Conditions
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An efficient Ir-catalyzed amidation of indoles with sulfonyl azides is disclosed, affording diverse C4-amidated indoles exclusively under mild conditions. In this protocol, a variety of indoles with commonly occurring functional groups such as formyl, acetyl, carboxyl, amide, and ester at the C3 position are well tolerated.
- Chen, Shuyou,Feng, Boya,Zheng, Xuesong,Yin, Jiangliang,Yang, Shiping,You, Jingsong
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supporting information
p. 2502 - 2505
(2017/05/24)
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- Discovery of a highly selective FLT3 kinase inhibitor from phenotypic cell viability profiling
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We discovered a novel molecular framework 4 containing a heterobiaryl pyrazolopyridine moiety as a selective FLT3 kinase inhibitor from phenotype-based viability profiling. Compound 4g showed outstanding selectivity in cellular cytotoxicity against MV-4-11 leukemic cells via the induction of apoptosis. The hypothesis-driven deconvolution elucidated that compound 4g selectively blocked the phosphorylation of FLT3 and its downstream effectors, such as ERK and STAT5, only in MV-4-11 cells. The inhibitory effect of 4g on in vitro enzyme function and FLT3 phosphorylation in cells proved that FLT3 kinase is a direct molecular target of 4g. Finally, the kinase activity profiling of 4g verified its excellent selectivity toward FLT3 over 40 representative kinases, including the receptor tyrosine kinase (RTK) family. The Royal Society of Chemistry 2013.
- Lee, Sanghee,Jo, Ala,Park, Seung Bum
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p. 228 - 232
(2013/03/14)
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- Glucocorticoid Mimetics, Methods of Making Them, Pharmaceutical Compositions and Uses Thereof
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Compounds of Formula (I) wherein R1, R2, R3, R4, R5, R6, and R7 are as defined herein, or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.
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Page/Page column 44
(2010/12/29)
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- An efficient one-step synthesis of heterobiaryl pyrazolo[3,4-u] pyridines via indole ring opening
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A mild one-step synthetic method to access privileged heterobiaryl pyrazolo[3,4-b]pyridines from indole-3-carboxaldehyde derivatives and a variety of aminopyrazoles has been developed. This novel method constructs heterobiaryls with the wide scope of substrate generality and excellent regioselectivity via indole ring opening.
- Lee, Sanghee,Park, Seung Bum
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supporting information; experimental part
p. 5214 - 5217
(2010/03/04)
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- Inhibitors of cellular necrosis
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The present invention relates to compounds and pharmaceutical preparations and their use in therapy for preventing or treating trauma, ischemia, stroke and degenerative diseases associated with cell death. Methods and compositions of the invention are particularly useful for treating neurological disorders associated with cellular necrosis.
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Page/Page column 37
(2008/06/13)
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- Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors
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A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined
- Mattson, Ronald J.,Catt, John D.,Denhart, Derek J.,Deskus, Jeffrey A.,Ditta, Jonathan L.,Higgins, Mendi A.,Marcin, Lawrence R.,Sloan, Charles P.,Beno, Brett R.,Gao, Qi,Cunningham, Melissa A.,Mattson, Gail K.,Molski, Thaddeus F.,Taber, Matthew T.,Lodge, Nicholas J.
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p. 6023 - 6034
(2007/10/03)
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