NHE1 inhibitor
BI-9627
BI-9627 is a highly potent sodium−hydrogen exchanger isoform 1 (NHE1) inhibitor (IC50 = 6 nM). It shows good selectivity against NHE2 and NHE3, low potential of drug-drug interactions, low potency for potassium channels such as hERG, and excellent pharmacokinetics following intravenous administration in rodent models (rat). This compound is suitable for both in vitro and in vivo experiments.
More information
Sodium−hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for the regulation of intracellular pH via the electroneutral exchange of sodium ions and protons2.
NHE1 is a member of a family of such proteins which encompasses nine variously expressed isoforms. While NHE1 is ubiquitously expressed3, it is the predominant NHE present in myocardial tissue where it plays a central role in the regulation of intracellular pH in cardiomyocytes4.
BI-9627 shows remarkably potent activity in the isolated heart model of ischemia-reperfusion injury (Compound 60 in reference 1)1.
X-ray Structure of an ion channel (nitrate channel from Salmonella typhimurium, PDB code: 4FC4)
BI-9627 shows an IC50 of 6 nM in the pHi change assay and an IC50 of 31 nM in the human platelet swelling inhibition (hPSA) assay1.
| Probe name / negative control | BI-9627 | BI-0054 |
| MW [Da, free base]a | 356.3 | 382.4 |
| pHi change NHE1 (IC50) [nM] | 6 | >10,000 |
| pHi change NHE2 (IC50) [nM] | 231 | >10,000 |
| pHi change NHE3 (IC50) [nM] | >16,000 | >10,000 |
| hPSA (IC50) [nM] | 31 | >10,000 |
| rPSA (IC50) [nM] | 138 | n.d. |
a For the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
The molecule shows low DDI potential as measured by CYP inhibition, CYP 3A4 inactivation, and PXR mediated CYP 3A4 induction, low hERG potency with concomitant absence of effects in lengthening action potential duration.
| Probe name / negative control | BI-9627 | BI-0054 | ||
| Solubility @ pH 7 [µg/mL] | 90.5 | >38 | ||
| LogD @ pH 7.4 | 2.0 | 1.6 | ||
| PAMPA rating | high | n.a. | ||
| Microsomes stability [% QH] (human/rat) | <11 / 11 | <30 / n.a. | ||
| Hepatocyte stability [% QH] (human/rat) | 16 / 1 | n.a. | ||
| Plasma Protein Binding [% QH] (human/rat) | 77.4 / 92 | n.a. | ||
| Cytotoxicity [µM] | >100 | n.a. | ||
| hERG (IC50) [µM] | >77 | n.a. | ||
| Phospholipidosis [µM] | >50 | n.a. | ||
| Cyp inhibition 2C19 [µM] | >30 | n.a. | ||
| Cyp inhibition 2C9 [µM] | >30 | n.a. | ||
| Cyp inhibition 2D6 [µM] | >30 | n.a. | ||
| Cyp inhibition 3A4 [µM] | >30 | n.a. | ||
| AMES Q 5µg/plate directly | negative | n.a. | ||
| AMES Q 5µg/plate S9 | negative | n.a. | ||
| Probe name | BI-9627 | |
| Species | rata | dogb |
| F [%] | 73 | 33 |
| Clearance [% QH] | 5.7 | 13 |
| Vss [L/kg] | 0.76 | 1.4 |
| Mean residence time after i.v. dose [h] | 3.2 | 6.2 |
a i.v. dose: 1 mg/kg, p.o. dose: 10mg/kg
b i.v. dose: 1 mg/kg, p.o. dose: 5mg/kg
BI-0054 is a close analog of BI-9627 but is inactive against NHE1, NHE2 and NHE3 in the pHi change assay (all > 10,000 nM). BI-0054 can be ordered as negative control compound.
BI-0054, negative control
NHE isoform selectivity: BI-9627 shows > 30-fold selectivity against NHE2 and NHE3.
Eurofins Safety Panel 44™ screen on 68 targets @ 10 µM did not give strong hits.
| SELECTIVITY DATA AVILABLE | BI-9627 | BI-0054 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| PDSP5 | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Assay conditions can be found in reference 1.
Download selectivity data:
BI-9627_selectivityData.xlsx
BI-0054_selectivityData.xlsx
See reference 1
BI-9627 is a highly potent NHE1 inhibitor with low DDI potential, excellent pharmacokinetics, and good selectivity against NHE2 and NHE3.
Identification of a Potent Sodium Hydrogen Exchanger Isoform 1 (NHE1) Inhibitor with a Suitable Profile for Chronic Dosing and Demonstrated Cardioprotective Effects in a Preclinical Model of Myocardial Infarction in the Rat
Huber J. D., Bentzien J., Boyer S. J., Burke J., De Lombaert S., Eickmeier C., Guo X., Haist J. V., Hickey E. R., Kaplita P., Karmazyn M., Kemper R., Kennedy C. A., Kirrane T., Madwed J. B., Mainolfi E., Nagaraja N., Soleymanzadeh F., Swinamer A., Eldrup A. B.
J. Med. Chem. 2012, 55, 7114-7140.
Molecular cloning of putative members of the Na/H exchanger gene family: cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins
Orlowski J, Kandasamy R. A., Shull G. E.
J. Biol. Chem. 1992, 267, 9331−9339.
When you plan a publication, please use the following acknowledgement:
BI-9627 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.