- Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors
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Synthesis, biological evaluation, and SAR dependencies for a series of novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors of GSK-3β kinase are described. The inhibitory activity of the synthesized compounds is highly dependent on the character of substituents in the phenyl ring and the nature of terminal heterocyclic fragment of the core molecular scaffold. The most potent compounds from this series contain 3,4-di-methyl or 2-methoxy substituents within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-oxadiazole heterocycle. These compounds selectively inhibit GSK-3β kinase with IC50 value of 0.35 and 0.41 μM, respectively.
- Koryakova, Angela G.,Ivanenkov, Yan A.,Ryzhova, Elena A.,Bulanova, Elena A.,Karapetian, Ruben N.,Mikitas, Olga V.,Katrukha, Eugeny A.,Kazey, Vasily I.,Okun, Ilya,Kravchenko, Dmitry V.,Lavrovsky, Yan V.,Korzinov, Oleg M.,Ivachtchenko, Alexandre V.
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supporting information; experimental part
p. 3661 - 3666
(2009/04/16)
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- Oxadiazole-carbonylaminothioureas as SIRT1 and SIRT2 inhibitors
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A new inhibitor for human sirtuin type proteins 1 and 2 (SIRT1 and SIRT2) was discovered through virtual database screening in search of new scaffolds. A series of compounds was synthesized based on the hit compound (3-[[3-(4-tert-butylphenyl)1,2,4-oxadiazole-5-carbonyl]ammo]-1-[3- (trifluoromethyl)phenyl]thiourea). The most potent compound in the series was nearly as potent as the reference compound (6-chloro-2,3,4,9-tetrahydro-1H- carbazole-1-carboxamide).
- Huhtiniemi, Tero,Suuronen, Tiina,Rinne, Valtteri M.,Wittekindt, Carsten,Lahtela-Kakkonen, Maija,Jarho, Elina,Wallén, Erik A. A.,Salminen, Antero,Poso, Antti,Lepp?nen, Jukka
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supporting information; experimental part
p. 4377 - 4380
(2009/06/17)
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- Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro- (7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABAAα5 benzodiazepine binding site
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The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)- 1,2,4-triazolo[3,4-a]phthalazines as GABAAα5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of α5- over α1-, α2-, and α3-containing GABAA receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABAAα5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4- triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABAAα5 subtype with functional selectivity over the other GABAA receptor subtypes and good oral bioavailability.
- Street, Leslie J.,Sternfeld, Francine,Jelley, Richard A.,Reeve, Austin J.,Carling, Robert W.,Moore, Kevin W.,McKernan, Ruth M.,Sohal, Bindi,Cook, Susan,Pike, Andrew,Dawson, Gerard R.,Bromidge, Frances A.,Wafford, Keith A.,Seabrook, Guy R.,Thompson, Sally A.,Marshall, George,Pillai, Goplan V.,Castro, José L.,Atack, John R.,MacLeod, Angus M.
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p. 3642 - 3657
(2007/10/03)
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