Premium
Pyrrolo[1,2‐ a ]quinoxalines: Insulin Mimetics that Exhibit Potent and Selective Inhibition against Protein Tyrosine Phosphatase 1B
Author(s) -
GarcíaMarín Javier,
Griera Mercedes,
SánchezAlonso Patricia,
Di Geronimo Bruno,
Mendicuti Francisco,
RodríguezPuyol Manuel,
Alajarín Ramón,
PascualTeresa Beatriz,
Vaquero Juan J.,
RodríguezPuyol Diego
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000446
Subject(s) - druggability , chemistry , insulin receptor , allosteric regulation , enzyme , docking (animal) , phosphorylation , protein tyrosine phosphatase , biochemistry , insulin , selectivity , phosphatase , stereochemistry , biology , insulin resistance , medicine , nursing , gene , endocrinology , catalysis
PTP1B dephosphorylates insulin receptor and substrates to modulate glucose metabolism. This enzyme is a validated therapeutic target for type 2 diabetes, but no current drug candidates have completed clinical trials. Pyrrolo[1,2‐ a ]quinoxalines substituted at positions C1–C4 and/or C7–C8 were found to be nontoxic to cells and good inhibitors in the low‐ to sub‐micromolar range, with the 4‐benzyl derivative being the most potent inhibitor (0.24 μ m ). Some analogues bearing chlorine atoms at C7 and/or C8 kept potency and showed good selectivity compared to TCPTP (selectivity index >40). The most potent inhibitors behaved as insulin mimetics by increasing glucose uptake. The 4‐benzyl derivative inhibited insulin receptor substrate 1 and AKT phosphorylation. Molecular docking and molecular dynamics simulations supported a putative binding mode for these compounds to the allosteric α3/α6/α7 pocket, but inconsistent results in enzyme inhibition kinetics were obtained due to the high tendency of these inhibitors to form stable aggregates. Computational calculations supported the druggability of inhibitors.