NHE1 inhibitor | BI-9627
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Highlights
BI-9627 shows high sodium−hydrogen exchanger isoform 1 (NHE1) potency, 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, excellent pharmacokinetics in rat and dog, and remarkably potent activity in the isolated heart model of ischemia-reperfusion injury (Compound 60 in reference 1).1 The compound also shows good selectivity against NHE2 and NHE3 and did not show strong hits in a Eurofins-Panlabs® screen.
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Target 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 protons.2
NHE1 is a member of a family of such proteins which encompasses nine variously expressed isoforms. While NHE1 is ubiquitously expressed,3 it is the predominant NHE present in myocardial tissue where it plays a central role in the regulation of intracellular pH in cardiomyocytes.4
Structure of an ion channel (nitrate channel from Salmonella typhimurium, PDB code: 4FC4)
In vitro Activity
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) assay.1
|
Probe name / Negative control |
BI-9627 |
BI-0054 |
|
MW [Da] |
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 |
- |
In vitro DMPK parameters
|
Probe name / Negative control |
BI-9627 |
BI-0054 |
||
|
Solubility @ pH 7 [µg/ml] |
90.5 |
>38 |
||
|
LogD (pH 7.4) |
2.0 |
- |
||
|
PAMPA rating |
high |
- |
||
|
Microsomes [% QH] human / rat |
<11 |
11 |
<30 |
- |
|
Hepatocyte clearance [% QH] human / rat |
17 |
6 |
- |
|
|
Plasma protein binding [% QH] human / rat |
77.4 |
92 |
- |
|
|
Cytotoxicity [µM] |
>100 |
- |
||
|
hERG PatchExpress [µM] |
>30 |
- |
||
|
Phospholipidosis [µM] |
>50 |
- |
||
|
Cyp inhibition 2C19 [µM] |
>30 |
- |
||
|
Cyp inhibition 2C9 [µM] |
>30 |
- |
||
|
Cyp inhibition 2D6 [µM] |
>30 |
- |
||
|
Cyp inhibition 3A4 [µM] |
>30 |
- |
||
|
AMES Q 5µg/plate directly |
negative |
- |
||
|
AMES Q 5µg/plate S9 |
negative |
- |
||
In vivo DMPK parameters
|
Probe name |
BI-9627 |
|
|
F [%] rat / dog |
73 |
33 |
|
CL [% QH] rat / dog |
5.7 |
13 |
|
Vss [l/kg] rat / dog |
0.76 |
1.4 |
|
MRT [h] rat / dog |
3.2 |
6.2 |
Pharmacokinetic parameters of BI-9627 upon iv application of 1 mg/kg
Negative control
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
Selectivity
NHE isoform selectivity: BI-9627 shows >30 fold selectivity against NHE2 and NHE3.
Eurofins-Panlabs® screen on 68 targets @ 10 µM did not give strong hits. Selectivity data is available.
|
Probe name |
BI-9627 |
|
Cerep® |
No |
|
Eurofins-Panlabs® |
Yes |
|
Invitrogen® |
No |
|
DiscoverX |
No |
|
Dundee |
No |
Assay conditions can be found in reference 1.
reference molecules
See reference 1
Summary
BI-9627 is a highly potent NHE1 inhibitor with low DDI potential, excellent pharmacokinetics, and good selectivity against NHE2 and NHE3.
Supplementary data
References
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.
The myocardial Na+ −H+ exchanger: Structure, regulation, and its role in heart disease
Karmazyn, M.; Gan, X. T.; Humphreys, R. A.; Yoshida, H.; Kusumoto, K.
Circ. Res. 1999, 85, 777−786.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.Molecular biology of the cardiac sodium/hydrogen exchanger
Fliegel, L.; Dyck, J. R. B.
Cardiovasc. Res. 1995, 29, 155−159.
