Pyrrolo[1,2-a]quinoxalines: Insulin Mimetics that Exhibit Potent and Selective Inhibition against Protein Tyrosine Phosphatase 1B.
Animals
Cell Differentiation
/ drug effects
Cell Line
Cell Survival
/ drug effects
Diabetes Mellitus, Type 2
/ drug therapy
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ chemical synthesis
Glucose
/ metabolism
Hep G2 Cells
Humans
Insulin
/ metabolism
Mice
Models, Molecular
Molecular Structure
Protein Tyrosine Phosphatase, Non-Receptor Type 1
/ antagonists & inhibitors
Pyrroles
/ chemical synthesis
Quinoxalines
/ chemical synthesis
Structure-Activity Relationship
PTP1B
biological activity
inhibitors
insulin mimetics
pyrrolo[1,2-a]quinoxaline
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
05 10 2020
05 10 2020
Historique:
received:
20
06
2020
revised:
29
07
2020
pubmed:
11
9
2020
medline:
31
7
2021
entrez:
10
9
2020
Statut:
ppublish
Résumé
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 μm). 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.
Identifiants
pubmed: 32909701
doi: 10.1002/cmdc.202000446
doi:
Substances chimiques
Enzyme Inhibitors
0
Insulin
0
Pyrroles
0
Quinoxalines
0
pyrrolo(1,2-a)quinoxaline
0
PTPN1 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 1
EC 3.1.3.48
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1788-1801Informations de copyright
© 2020 Wiley-VCH GmbH.
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