26032-72-4Relevant articles and documents
Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
Soares De Melo, Candice,Singh, Vinayak,Myrick, Alissa,Simelane, Sandile B.,Taylor, Dale,Brunschwig, Christel,Lawrence, Nina,Schnappinger, Dirk,Engelhart, Curtis A.,Kumar, Anuradha,Parish, Tanya,Su, Qin,Myers, Timothy G.,Boshoff, Helena I. M.,Barry, Clifton E.,Sirgel, Frederick A.,Van Helden, Paul D.,Buchanan, Kirsteen I.,Bayliss, Tracy,Green, Simon R.,Ray, Peter C.,Wyatt, Paul G.,Basarab, Gregory S.,Eyermann, Charles J.,Chibale, Kelly,Ghorpade, Sandeep R.
supporting information, p. 719 - 740 (2021/02/03)
Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy
Vuorinen, Aini,Wilkinson, Isabel V.L.,Chatzopoulou, Maria,Edwards, Ben,Squire, Sarah E.,Fairclough, Rebecca J.,Bazan, Noelia Araujo,Milner, Josh A.,Conole, Daniel,Donald, James R.,Shah, Nandini,Willis, Nicky J.,Martínez, R. Fernando,Wilson, Francis X.,Wynne, Graham M.,Davies, Stephen G.,Davies, Kay E.,Russell, Angela J.
supporting information, (2021/05/03)
Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid.
TRISUBSTITUTED PYRIMIDINE COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CANCER, RETINAL DISORDERS, AND CARDIOMYOPATHIES
-
Page/Page column 33; 34, (2018/11/26)
The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof: It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses, in particular in the treatment of
