ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles

0476344 - ÚEB 2018 RIV FR eng J - Journal Article
Řezníčková, Eva - Tenora, L. - Pospíšilová, Pavlína - Galeta, J. - Jorda, Radek - Berka, K. - Majer, Pavel - Potáček, M. - Kryštof, Vladimír
ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles.
European Journal of Medicinal Chemistry. Roč. 127, FEB 15 (2017), s. 632-642. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA MŠMT(CZ) LO1204; GA ČR(CZ) GA15-15264S; GA MŠMT(CZ) LM2015047
Institutional support: RVO:61389030 ; RVO:61388963
Keywords : i-receptor kinase * beta signaling pathway * small-molecule inhibitor * tgf-beta * domain inhibitors * growth * fibrosis * cancer * potent * series * Transforming growth factor beta receptor I * Protein kinase * Inhibitor * Substituted pyrrolo[1,2-b]pyrazoles
OECD category: Pharmacology and pharmacy; Pharmacology and pharmacy (UOCHB-X)
Impact factor: 4.816, year: 2017

A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGF beta Tap and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.
Permanent Link: http://hdl.handle.net/11104/0272863