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Discovery and evaluation of biphenyl derivatives of 2‐iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity

This work describes the synthesis of series hydrobromides of N‐(4‐biphenyl)methyl–N′‐dialkylaminoethyl‐2‐iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi‐privileged structures. Compound 7a proved to...

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Published in:Chemical biology & drug design 2023-04, Vol.101 (4), p.896-914
Main Authors: Babkov, Denis A., Zhukovskaya, Olga N., Brigadirova, Anastasia A., Prilepskaya, Diana R., Kolodina, Alexandra A., Abbas, Abbas Haider S., Morkovnik, Anatolii S., Sobhia, M. Elizabeth, Ghosh, Ketan, Spasov, Alexander A.
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container_end_page 914
container_issue 4
container_start_page 896
container_title Chemical biology & drug design
container_volume 101
creator Babkov, Denis A.
Zhukovskaya, Olga N.
Brigadirova, Anastasia A.
Prilepskaya, Diana R.
Kolodina, Alexandra A.
Abbas, Abbas Haider S.
Morkovnik, Anatolii S.
Sobhia, M. Elizabeth
Ghosh, Ketan
Spasov, Alexander A.
description This work describes the synthesis of series hydrobromides of N‐(4‐biphenyl)methyl–N′‐dialkylaminoethyl‐2‐iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi‐privileged structures. Compound 7a proved to activate AMP‐activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual‐target mechanism of action. Using prove of concept in vivo study, we show that dual‐targeting compound 7a has a disease‐modifying effect in a rat model of type 2 diabetes mellitus via improving insulin sensitivity and lipid metabolism. Biphenyl derivative of 2‐iminobenzimidazole acts as a high‐micromolar AMPK activator and PTP1B inhibitor with a disease‐modifying effect in a rat model of type 2 diabetes mellitus via improving insulin sensitivity and lipid metabolism.
doi_str_mv 10.1111/cbdd.14198
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source Wiley-Blackwell Read & Publish Collection
subjects AMP-Activated Protein Kinases - metabolism
AMPK
Animals
Biphenyl Compounds
diabetes mellitus
Diabetes Mellitus, Type 2 - metabolism
Enzyme Inhibitors - chemistry
Hypoglycemic Agents - chemistry
obesity
Protein Tyrosine Phosphatase, Non-Receptor Type 1
PTP1B
Rats
title Discovery and evaluation of biphenyl derivatives of 2‐iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity
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