Synonym
GLPG-1837; GLPG 1837; GLPG1837; ABBV-974; ABBV 974; ABBV974
IUPAC/Chemical Name
N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide
InChi Key
GHTGYZMBQPXTCQ-UHFFFAOYSA-N
InChi Code
InChI=1S/C16H20N4O3S/c1-15(2)7-8-10(12(17)21)14(24-11(8)16(3,4)23-15)19-13(22)9-5-6-18-20-9/h5-6H,7H2,1-4H3,(H2,17,21)(H,18,20)(H,19,22)
SMILES Code
O=C(C1=NNC=C1)NC(S2)=C(C(N)=O)C3=C2C(C)(C)OC(C)(C)C3
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators).
Biological target:
GLPG1837 is a potent and reversible CFTR potentiator, with EC50s of 3 nM and 339 nM for F508del and G551D CFTR, respectively.
In vitro activity:
As a first step to characterize GLPG1837, this study examined the effect of acute addition of this compound to macroscopic WT-CFTR currents preactivated with PKA and ATP to a steady state at a holding potential of −30 mV in excised inside-out patches. Fig. 2 A shows a representative real-time recording in which an application of 3 µM GLPG1837 in the continuous presence of ATP enhances the currents by 2.06 ± 0.08-fold (n = 19). This potentiation effect is reversible and concentration dependent. The dose responses at different concentrations of GLPG1837 were normalized to the currents at 3 µM GLPG1837 in the same patch, and the data can be fitted with the Hill equation, yielding a K1/2 of 0.23 ± 0.12 µM and a Hill coefficient of 0.70 ± 0.24 (Fig. 2 B).
Reference: J Gen Physiol. 2017 Dec 4; 149(12): 1105–1118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715911/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
159.5 |
457.78 |
| Ethanol |
5.0 |
14.35 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
348.42
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Yeh HI, Sohma Y, Conrath K, Hwang TC. A common mechanism for CFTR potentiators. J Gen Physiol. 2017 Dec 4;149(12):1105-1118. doi: 10.1085/jgp.201711886. Epub 2017 Oct 27. PMID: 29079713; PMCID: PMC5715911.
In vitro protocol:
1. Yeh HI, Sohma Y, Conrath K, Hwang TC. A common mechanism for CFTR potentiators. J Gen Physiol. 2017 Dec 4;149(12):1105-1118. doi: 10.1085/jgp.201711886. Epub 2017 Oct 27. PMID: 29079713; PMCID: PMC5715911.
1: Van der Plas SE, Kelgtermans H, De Munck T, Martina SLX, Dropsit S, Quinton E, De Blieck A, Joannesse C, Tomaskovic L, Jans M, Christophe T, van der Aar E, Borgonovi M, Nelles L, Gees M, Stouten P, Van Der Schueren J, Mammoliti O, Conrath K, Andrews M. Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyr azole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High Extent. J Med Chem. 2018 Feb 22;61(4):1425-1435. doi: 10.1021/acs.jmedchem.7b01288. Epub 2018 Jan 10. PubMed PMID: 29148763.
2: DeStefano S, Gees M, Hwang TC. Physiological and pharmacological characterization of the N1303K mutant CFTR. J Cyst Fibros. 2018 Sep;17(5):573-581. doi: 10.1016/j.jcf.2018.05.011. Epub 2018 Jun 7. PubMed PMID: 29887518.
3: Gees M, Musch S, Van der Plas S, Wesse AS, Vandevelde A, Verdonck K, Mammoliti O, Hwang TC, Sonck K, Stouten P, Swensen AM, Jans M, Van der Schueren J, Nelles L, Andrews M, Conrath K. Identification and Characterization of Novel CFTR Potentiators. Front Pharmacol. 2018 Oct 26;9:1221. doi: 10.3389/fphar.2018.01221. eCollection 2018. PubMed PMID: 30416447; PubMed Central PMCID: PMC6212544.
