Development of DANDYs, New 3,5-Diaryl-7-azaindoles Demonstrating Potent DYRK1A Kinase Inhibitory Activity.

Stéphanie Gourdain , Julien Dairou , Clément Denhez , Linh Chi Bui , Fernando Rodrigues-Lima , Nathalie Janel , Jean M Delabar , Kevin Cariou (1) , Robert H Dodd (1)

1 ICSN - Institut de Chimie des Substances Naturelles

A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j-l) demonstrated high inhibitory potencies with Kis in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10(-6) M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3.

Mots clés: DYRK1A; Down Syndrome; Alzheimer's Disease; 7-Azaindoles

Domaines: Chimie organique

Stéphanie Gourdain, Julien Dairou, Clément Denhez, Linh Chi Bui, Fernando Rodrigues-Lima, et al.. Development of DANDYs, New 3,5-Diaryl-7-azaindoles Demonstrating Potent DYRK1A Kinase Inhibitory Activity.. Journal of Medicinal Chemistry, 2013, 56 (23), pp.9569-9585. ⟨10.1021/jm401049v⟩. ⟨hal-00933939⟩