380653-63-4Relevant academic research and scientific papers
Alkylation studies on pyrazolyl and isoxazolyl benzimidazoles
Kumar, Kishore,Hemasunder,Naidu,Dubey
, p. 393 - 398 (2013/09/24)
2-Acetylbenzimidazole (1) on heating with dimethyl formamide dimethyl acetal gave 1-(1 H-benzimidazolyl)-3-dimethylaminopropenone (2) which on reaction with hycirazpne hydrate gave 2-(1 H-pyrazolyl)-1 H-benzimidazole (3), The reaction of 3 with DMS/DES/ PhCH2CI in CH3CN containing K2CO3 as base and triethylbenzylammonium chloride (TEBAC) as phase trasfer catalyst (PTC) resulted in the formation of 2-(3-pyrazolyl)-1 - substitutedbenzimidazole (4). Alkylation of I with DMS/DES/PhCH2CI under PTC conditions gave the previously known 1-substituted -2-acetyl benzimidazoles (5) which with DMF-DMA gave I -substituted-2-(2-benzimidazolyl)-3.dimethylaminopropenone (6). The latter could also be obtained from 2 by alkylation under PTC conditions. Treatment of 6 with hydrazine hydrate in methanol yielded 4. Reaction of 2 with hydroxylammonium chloride yielded 1 H-(2-benzimidazolyl)-3-isoxazole (8) which on alkylation under PTC conditions gave 1-substituted (2-benzimidazolyl)-3-isoxazole (9). The latter could also be obtained from 6 by treatment with hydroxylammonium chloride.
Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H- pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design
Wyatt, Paul G.,Woodhead, Andrew J.,Berdini, Valerio,Boulstridge, John A.,Carr, Maria G.,Cross, David M.,Davis, Deborah J.,Devine, Lindsay A.,Early, Theresa R.,Feltell, Ruth E.,Lewis, E. Jonathan,McMenamin, Rachel L.,Navarro, Eva F.,O'Brien, Michael A.,O'Reilly, Marc,Reule, Matthias,Saxty, Gordon,Seavers, Lisa C. A.,Smith, Donna-Michelle,Squires, Matt S.,Trewartha, Gary,Walker, Margaret T.,Woolford, Alison J.-A.
supporting information; experimental part, p. 4986 - 4999 (2009/08/16)
The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
