5-(Indol-2-yl)pyrazolo[3,4-b]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis

Molecules

Thomas Müller¹  Wendy González²  Pedro De-la-Torre³  Jairo Quiroga⁴  Melissa Mejia-Gutierrez⁴  Braulio Insuasty⁴  Aytug K. Kiper⁵  Susanne Rinné⁵  Niels Decher⁵  David Ramírez⁶  Magdalena Platzk⁷ 

[1] Bayer AG, Research & Development, Pharmaceuticals, D-42096 Wuppertal, Germany;Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Poniente No. 1141, Talca 3460000, Chile;Department of Otolaryngology, Harvard Medical School and Massachusetts Eye and Ear, 243 Charles St, Boston, MA 02114, USA;Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A, Cali 760031, Colombia;Institute for Physiology and Pathophysiology, Vegetative Physiology and Center for Mind, Brain and Behavior (CMBB), Philipps-University of Marburg, Deutschhausstraße 2, 35037 Marburg, Germany;Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Llano Subercaseaux 2801-Piso 5, Santiago 8900000, Chile;Joint Pulmonary Drug Discovery Lab Bayer-MGH, Boston, MA 02114, USA;

关键词: TASK-3 channel blockers;    pyrazolo[3,4-b]pyridines;    molecular docking;    drug design;    pharmacophore;   

DOI  :  10.3390/molecules26133897

来源: DOAJ

【 摘 要 】

TASK channels belong to the two-pore-domain potassium (K_2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader—Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC₅₀ ≈ 30 μM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers.

【 授权许可】

Unknown