Glyburide

Protein target name:

ABCC8, KCNJ11

Mechanism of action:

Inhibitor

Probe Information

Target and Probe Information

Target Details

Target class:

Ion channel

Subclass:

Potassium channel

HUGO ID:

HGNC:59 HGNC:6257

Entrez gene ID:

6833 3767

UNIPROT ID:

Q09428 Q14654

Target alias:

ABC36, HHF1, HI, HRINS, MRP8, PHHI, SUR, SUR1, SUR1delta2, TNDM2, BIR, HHF2, IKATP, KIR6.2, MODY13, PHHI, TNDM3

Probe Details

Chemical Probes Portal ID:

CPP1805

Probe alias:

Glibenclamide; Glybenclamide; Diabeta; Micronase

PubChem CID:

3488

ChEMBL ID:

CHEMBL472

SMILES string:

COc1ccc(Cl)cc1C(=O)NCCc2ccc(cc2)S(=O)(=O)NC(=O)NC3CCCCC3

InChi Key:

ZNNLBTZKUZBEKO-UHFFFAOYSA-N

Orthogonal probe:

Repaglinide

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

4.3 nM

Potency assay:

Inhibition of human SUR1/Kir6.2 expressed in CHO cells. More data available in ChEMBL.

Off target activity

Potency (off target):

IC50

Off target protein and potency:

ABCC9: 220 nMSLCO1B1: 1,400 nMABCB11: 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).

In cell validation

On target activity in cells

Potency in cells:

EC50

3 nM

Potency assay (cells):

Stimulation of insulin secretion in rat INS-1E cells after 1 hr by alphaLISA assay in presence of 5 mM glucose (Bioorg. Med. Chem. Lett., (2014) 24:4:1031). In HIT (hamster beta cell line) cells, glyburide stimulates insulin secretion with ED50=0.4 nM.

Target engagement assay (cells):

In HIT cells, an iodinated version of glyburide photolabeled ABCC8; this labeling was blocked by unmodified glyburide.

Off target activity in cells

Probe Selectivity in Cell:

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).

In vivo validation

Organism:

Rat (Wistar and Goto-Kakizaki, relied on human PK data, PMID: 6767639)Mouse

Dose:

0.4 mg/Kg10 mg/Kg1 mg/Kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

Heart, pancreas

Primary Reference

Reference (doi):

10.1016/j.metabol.2012.07.010 10.1016/s0026-0495(96)90297-8 10.1016/0024-3205(93)90448-c

Reference (PMID):

2110566 22587986 6767639

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB 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

Jun 2 2020 - 1:01pm

Glyburide

Probe Information

Target Details

ABC36, HHF1, HI, HRINS, MRP8, PHHI, SUR, SUR1, SUR1delta2, TNDM2, BIR, HHF2, IKATP, KIR6.2, MODY13, PHHI, TNDM3

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Glyburide

Probe Information

Target Details

ABC36, HHF1, HI, HRINS, MRP8, PHHI, SUR, SUR1, SUR1delta2, TNDM2, BIR, HHF2, IKATP, KIR6.2, MODY13, PHHI, TNDM3

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?