Esther Carrasco, Patricia Gomez-Gutierrez, Pedro M. Campos, Miguel Vega, Angel Messeguer and Juan Jesus Perez* Pages 1640 - 1653 ( 14 )
Introduction: In the quest for novel allosteric inhibitors of the p38 MAP kinase, we recently described the A-loop regulatory site, identified by means of molecular modeling studies together with the disclosure of a small molecule hit with a moderate inhibitory profile. Starting from this structure, we subsequently identified two additional hits with simpler molecular structures from an in silico screening study, using a substructure search in the SciFinder database. After corroboration of their inhibitory profile, analysis of their structures permitted to conclude about the suitability of the [1,2,5]oxadiazolo[3,4-b]pyrazine (furazano[ 3,4-b]pyrazine) scaffold for the development of potent A-loop regulatory site p38 MAP kinase inhibitors. Accordingly, we report the synthesis and pharmacological evaluation of a series of di-substituted analogs with a potent inhibitory profile of p38 MAP kinase, as shown by in vitro assays of their capability to inhibit IL-1β secretion in human monocyte-derived macrophages.
Objective: To find small molecule potent inhibitors of the p38 MAP kinase A-loop regulatory site.
Methods: Starting from this structure, we subsequently identified two additional hits with simpler molecular structures from an in silico screening study, using a substructure search in the SciFinder database. After corroboration of their inhibitory profile, we carried out a hit-tolead optimization process guided by molecular modeling using a [1,2,5]oxadiazolo[3,4- b]pyrazine (furazano[3,4-b]pyrazine) scaffold.
Results: We report the synthesis and pharmacological evaluation of a series of di-substituted analogs with a potent inhibitory profile of p38 MAP kinase, as shown by in vitro assays of their capability to inhibit IL-1β secretion in human monocyte-derived macrophages.
Conclusion: We describe in the present work a series of [1,2,5]oxadiazolo[3,4-b]pyrazine (furazano[3,4-b]pyrazine), which are potent inhibitors of IL-1β secretion in human monocytederived macrophages allosteric modulators of the p38 MAP kinase A-loop regulatory site.
Non-competitive kinase inhibitors, furazano[3,4-b]pyrazine derivatives, 1,2,5-oxadiazole derivatives, MAPK inhibitors, IL-1β inhibitors, kinome, orthosteric ligands.
Allinky Biopharma, Campus de Cantoblanco, Faraday 7, 28049 Madrid, Allinky Biopharma, Campus de Cantoblanco, Faraday 7, 28049 Madrid, Allinky Biopharma, Campus de Cantoblanco, Faraday 7, 28049 Madrid, Allinky Biopharma, Campus de Cantoblanco, Faraday 7, 28049 Madrid, IQAC CSIC, Institute of Advanced Chemistry of Catalonia, Dept. Biol. Chem., Jordi Girona 18-26, 08034 Barcelona, Dept. of Chemical Engineering, Universitat Politecnica de Catalunya, 08028 Barcelona