Structure-Activity Studies of Novel Di-substituted [1,2,5]oxadiazolo [3,4-b]pyrazine Analogs Targeting the A-loop Regulatory Site of p38
MAP Kinase

Esther      Carrasco; Patricia      Gomez-Gutierrez; Pedro   M.   Campos; Miguel      Vega; Angel      Messeguer; Juan   Jesus   Perez

doi:10.2174/0929867328666210712165659

Abstract

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.

Keywords: Non-competitive kinase inhibitors, furazano[3, 4-b]pyrazine derivatives, 1, 2, 5-oxadiazole derivatives, MAPK inhibitors, IL-1β inhibitors, kinome, orthosteric ligands.

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DOI https://dx.doi.org/10.2174/0929867328666210712165659	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X

Current Medicinal Chemistry

Structure-Activity Studies of Novel Di-substituted [1,2,5]oxadiazolo [3,4-b]pyrazine Analogs Targeting the A-loop Regulatory Site of p38 MAP Kinase

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