767343-19-1Relevant articles and documents
FUSED IMIDAZOLE COMPOUNDS
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Page/Page column 85-86, (2015/09/23)
The present invention provides compounds represented by formula (I), pharmaceutically acceptable salts thereof, N-oxides thereof, solvates thereof or prodrugs thereof (wherein the characters are as defined in the description). The compounds represented by formula (I) have affinity and selectivity for the gamma-aminobutyric acid A receptor subunit alpha 5 (GABAA α5) and act as GABAA α5 negative allosteric modulators (GABAA α5 NAM), so that they are useful in the prevention and/or treatment of diseases which are related to the GABAA α5 such as Alzheimer's disease.
Discovery of inhibitors of Trypanosoma brucei by phenotypic screening of a focused protein kinase library
Woodland, Andrew,Thompson, Stephen,Cleghorn, Laura A. T.,Norcross, Neil,De Rycker, Manu,Grimaldi, Raffaella,Hallyburton, Irene,Rao, Bhavya,Norval, Suzanne,Stojanovski, Laste,Brun, Reto,Kaiser, Marcel,Frearson, Julie A.,Gray, David W.,Wyatt, Paul G.,Read, Kevin D.,Gilbert, Ian H.
supporting information, p. 1809 - 1820 (2015/11/10)
A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm. Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H-imidazo[4,5-b]pyrazin-2(3H)-one scaffold that showed sub-micromolar activity and excellent selectivity against the MRC5 cell line. Subsequent rounds of optimisation led to the identification of compounds that exhibited good in vitro drug metabolism and pharmacokinetics (DMPK) properties, although in general this series suffered from poor solubility. A scaffold-hopping exercise led to the identification of a 1H-pyrazolo[3,4-b]pyridine scaffold, which retained potency. A number of examples were assessed in a T. b. brucei growth assay, which could differentiate static and cidal action. Compounds from the 1H-imidazo[4,5-b]pyrazin-2(3H)-one series were found to be either static or growth-slowing and not cidal. Compounds with the 1H-pyrazolo[3,4-b]pyridine scaffold were found to be cidal and showed an unusual biphasic nature in this assay, suggesting they act by at least two mechanisms. Focused on tipping the HAT: We report a phenotypic screen of a focused kinase library against Trypanosoma brucei and subsequent optimisation of a hit, with sub-micromolar activity, based on a 1H-imidazo[4,5-b]pyrazin-2(3H)-one scaffold. Scaffold hopping gave a second series based on a 1H-pyrazolo[3,4-b]pyridine scaffold, also with sub-micromolar activity. The first series of compounds were static or growth-slowing and not cidal, whilst those from the second series were cidal, but showed an unusual biphasic growth curve, suggestive of several mechanisms of action.
MLK INHIBITORS AND METHODS OF USE
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Page/Page column 79; 81-82; 84, (2010/07/02)
Provided are compounds having an inhibitory effect on Mixed Lineage Kinases. Also provided are pharmaceutical compositions, methods of preparing the compounds, synthetic intermediates, and methods of using the compounds, independently or in combination with other therapeutic agents, for treating diseases and conditions which are affected by Mixed Lineage Kinase inhibition. Also provided are methods of treatment of neuropsychiatric disorders which comprise the inhibition of Mixed Lineage Kinases.
COMPOUND LIBRARIES
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Page 114, (2010/02/08)
The present invention relates to compounds capable of binding to the active site of protein kinase enzymes. The invention further relates to libraries of compounds and a family of libraries of compounds for use in screening programmes against protein kinases as well as the individual compounds for use in hit to lead and lead optimisation projects, and similar stages in the drug discovery process. The invention also provides methods for making compounds and libraries.
