Synthesis, docking study and kinase inhibitory activity of a number of new substituted pyrazolo[3,4-c]pyridines

Meropi Sklepari , Nikolaos Lougiakis , Athanasios Papastathopoulos , Nicole Pouli , Panagiotis Marakos , Vassilios Myrianthopoulos (1, 2) , Thomas Robert (3, 4, 5) , Stéphane Bach (3, 4, 5) , Emmanuel Mikros (1) , Sandrine Ruchaud (4, 3)

1 Department of Pharmaceutical Chemistry
2 PharmaGnose S.A.
3 SBR - Station biologique de Roscoff = Roscoff Marine Station
4 LBI2M - Laboratoire de Biologie Intégrative des Modèles Marins
5 KISSf - Plate-forme de criblage d'inhibiteurs de protéines kinases=Kinase Inhibitor Specialized Screening facility

A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against GSK3α/β as well as against CLK1 and DYRK1A, with good selectivity and remarkable SARs, without being cytotoxic. Molecular simulations in corelation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent.

Mots clés: pyrazolopyridine; kinase inhibition; GSK3α/β; purine analogues; molecular simulations

Domaines: Sciences du Vivant [q-bio]; Chimie; Chimie organique

Meropi Sklepari, Nikolaos Lougiakis, Athanasios Papastathopoulos, Nicole Pouli, Panagiotis Marakos, et al.. Synthesis, docking study and kinase inhibitory activity of a number of new substituted pyrazolo[3,4-c]pyridines. Chemical and Pharmaceutical Bulletin, 2017, ⟨10.1248/cpb.c16-00704⟩. ⟨hal-03875290⟩