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Glyburide

Inhibitor of ABCC8, KCNJ11

Structure

Information

  • ABCC8
  • KCNJ11
  • Inhibitor

In Vitro Validations

Uniprot ID: Q09428
Target Class: Ion Channel
Target SubClass: Potassium channel
Potency: IC50
Potency Value: 4.3 nM
Potency Assay: Inhibition of human SUR1/Kir6.2 expressed in CHO cells. More data available in ChEMBL.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
ATP-binding cassette sub-family C member 8, SUR1, ...

DOI Reference: 10.1016/j.metabol.2012.07.010

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 ABCC9: 220 nM, SLCO1B1: 1,400 nM, ABCB11: 5,300 nM
Potency assay (off target): These are all values taken from ChEMBL. Please check ChEMBL and/or Probe Miner (http://probeminer.icr.ac.uk/#/Q09428/732) for details.
Probe Selectivity in Vitro:
Glyburide has been evaluated against CYPs (PMID: 12920163) with IC50s >40 uM, except CYP2C9 (IC50=2.4 uM).
Probe Selectivity in Vitro:
The compound is inactive against hERG, CFTR (PMID: 8770056) and a few other targets. Please check ChEMBL and Probe Miner (http://probeminer.icr.ac.uk/#/Q09428/732).
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 15 May 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Serum Glibenclamide in Diabetic Patients, and Influence of Food on the Kinetics and Effects of Glibenclamide is not useful to include for consideration as chemical probe (although is useful to list in extra info for use as clinical biomarker). It would have been more helpful to provide the refs that the data shown were extracted from and these should definitely be listed alongside the probe at the top. The mode of action of these sulfonyl ureas is clearly complex and its understanding has followed the appreciation of their clinical utility. This molecule is clearly able to regulate several ABC transporters by modulation of the K-ATP channels – but there is considerable discussion (e.g. doi: 10.1074/jbc.M110.155200) of block of other related channels – e.g. CFTR.

There is clear evidence that glibenclamide is a wide spectrum KATP blocker [https://pubs.acs.org/doi/pdf/10.1021/jm970762d; European Journal of Medicinal Chemistry 39 (2004) 835–847; Bioorganic & Medicinal Chemistry 11 (2003) 2099–2113) and that different in vivo responses are seen with other related compounds which have a narrower spectrum of KATP block (J. Med. Chem. 2001, 44, 1085-1098).

CFTR is inhibited by glibenclamide and less potently by a few other KATP channel blockers and openers (J Gen. Physiol., 100: 573-591, 1992). Glibenclamide also inhibits MRP1 (Br. J. Pharmacol., 132: 778-784, 2001) and P-gp (Pflugers. Arch., 437: 652-660, 1999), and it appears to be a substrate of the latter.

Therefore, this molecule is a useful blocker of the K-ATP channels (i.e. those containing 4 Kir6.x and 4 SUR subunits) – but there is limited information about the molecular mechanism of differential effects seen in different tissue/organelle type and additional evidence of blockade of other ABC transporters (CFTR, MRP1, PGP).

This is clearly a good probe candidate but from a single publication so far. The best identifier is https://pubchem.ncbi.nlm.nih.gov/compound/103828029.  The two melatonic receptor human paralogues  are well studied pharmacologically so additional compounds and controls are also available for comparative testing 

A curated selected listing of these can be found here  https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=288

(last updated: 2 Jun 2020 )