WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H555805
CAS#: 1401728-56-0
Description: NE52-QQ57 is an orally available GPR4 antagonist with an IC50 of 70 nM. NE 52-QQ57 significantly inhibited the AGE-induced increased expression of several key inflammatory cytokines and signaling molecules, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase 2 (COX2), and prostaglandin E2 (PGE2).
Hodoodo Cat#: H555805
Name: NE 52-QQ57
CAS#: 1401728-56-0
Chemical Formula: C24H28N6O
Exact Mass: 416.23
Molecular Weight: 416.530
Elemental Analysis: C, 69.21; H, 6.78; N, 20.18; O, 3.84
Synonym: NE52-QQ57; NE-52-QQ57; NE 52-QQ57; NE52QQ57; NE-52QQ57; NE 52QQ57;
IUPAC/Chemical Name: 2-(4-((2-ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole
InChi Key: HXPQWNPLNIEJOW-UHFFFAOYSA-N
InChi Code: InChI=1S/C24H28N6O/c1-4-21-20(22-26-15(2)13-16(3)30(22)29-21)14-17-5-7-18(8-6-17)23-27-28-24(31-23)19-9-11-25-12-10-19/h5-8,13,19,25H,4,9-12,14H2,1-3H3
SMILES Code: CCC1=NN(C(C)=CC(C)=N2)C2=C1CC3=CC=C(C4=NN=C(C5CCNCC5)O4)C=C3
Appearance: Solid powder
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: >3 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: Osteoarthritis (OA) is a common degenerative joint disease for which an effective therapeutic strategy has not yet been established. AGEs are widely recognized as a contributor to OA pathogenesis. GPR4, a recently discovered proton-sensing transmembrane receptor, has been shown to possess a wide range of physiological functions. However, the potential role of this receptor in chondrocytes and the pathogenesis of OA is unclear.
| Biological target: | NE 52-QQ57 is a selective, and orally available GPR4 antagonist with an IC50 of 70 nM. NE 52-QQ57 has anti-inflammatory activity. |
| In vitro activity: | The effect of NE 52-QQ57 on proton-mediated cAMP accumulation in cells over-expressing GPR4 was dependent on pH (Fig. 3A) and this dependence in the acidic range could be explained by competition with protons. NE 52-QQ57 (100nM) was maximally effective at pH 7.7 but approximately equally effective at pH 8.0 and 7.4. At pH 7.1, the potency of NE 52-QQ57 was reduced and at pH 6.8 NE 52-QQ57 (100nM) was ineffective. At pH 7.4, NE 52-QQ57 acts as a highly potent antagonist of GPR4 mediated cAMP accumulation with IC50 of 26.8nM (Fig. 3B). Reference: Neuropharmacology. 2018 Aug;138:381-392. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29894771/ |
| In vivo activity: | Minute ventilation (VE) which is the cumulative of RR and VT was not significantly affected at baseline by 20 mg kg−1 of NE-52-QQ57 in either rats (n = 8) or mice (n = 10). Relative to the vehicle (25% DMSO), NE-52-QQ57 significantly attenuated VE during hypercapnia at 5 and 10% CO2 in both species. For example, with 10% CO2 VE increased to 216 ± 11 a.u. in the group treated with vehicle, but only to 164 ± 18 a.u. in mice treated with NE-52-QQ57 (p < 0.001). Similarly, in rats at 10% CO2 VE increased to 662 ± 40 a.u. in the vehicle group, but to 568 ± 22 a.u. in the treated group (p < 0.001). Thus, in freely behaving mice and rats NE22-QQ57 blunted hypercapnic response to CO2. In anaesthetised rats, hypercapnia (10% CO2 in the inspired air) increased respiratory rate from 77 ± 9 to 94 ± 13 bursts/min (Fig. 6A), and this was not affected following systemic administration of NE 52-QQ57 (20 mg kg−1; n = 8, 76 ± 9 to 95 ± 12 bursts min−1; p = 0.92). NE 52-QQ57 had no effect on CO2-evoked increases in diaphragm EMG amplitude (0.25 ± 0.03 to 0.33 ± 0.04V cf. 0.25 ± 0.02 to 0.34 ± 0.03V; p = 0.94) and minute ventilation (19 ± 3 to 32±7A.U cf. 20 ± 3 to 33±6A.U; p = 0.88). Systemic NE 52-QQ57 also had no effect on basal respiratory rate (Fig. 6B). To additionally ensure that NE 52-QQ57 reaches the central GPR4 targets, the drug was then delivered directly on the ventral surface of the brainstem, where the RTN is located. Hypercapnia (10% CO2 in the inspired air) in 7 animals with denervated peripheral chemoreceptors increased respiratory frequency, phrenic nerve amplitude and minute ventilation (Fig. 6C). Hypercapnia increased the respiratory rate from 18 ± 6 to 40 ± 5 bursts min−1 following application of the vehicle on the ventral brainstem surface. CO2 had a similar effect in the presence of NE-52-QQ57 (1 mM) on the ventral brainstem surface (18 ± 4 to 41 ± 5 bursts min−1; p = 0.86, Fig. 6C). NE 52-QQ57 had no effect on other components of the hypercapnic respiratory response including increases in phrenic nerve burst amplitude (0.04 ± 0.01 to 0.06 ± 0.02V vs. 0.04 ± 0.02 to 0.06 ± 0.02V; p = 0.92) and minute ventilation (11 ± 4 to 34±8A.U vs. 11 ± 2 to 33±7A.U; p = 0.97). Direct application of NE 52-QQ57 to the ventral medulla had no effect on baseline respiratory activity (Fig. 6D). Reference: Neuropharmacology. 2018 Aug;138:381-392. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29894771/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 10.0 | 24.10 | |
| Ethanol | 45.0 | 108.00 |
The following data is based on the product molecular weight 416.53 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: | |
| In vitro protocol: | 1. Hosford PS, Mosienko V, Kishi K, Jurisic G, Seuwen K, Kinzel B, Ludwig MG, Wells JA, Christie IN, Koolen L, Abdala AP, Liu BH, Gourine AV, Teschemacher AG, Kasparov S. CNS distribution, signalling properties and central effects of G-protein coupled receptor 4. Neuropharmacology. 2018 Aug;138:381-392. doi: 10.1016/j.neuropharm.2018.06.007. Epub 2018 Jun 9. PMID: 29894771; PMCID: PMC6063991. |
| In vivo protocol: | 1. Hosford PS, Mosienko V, Kishi K, Jurisic G, Seuwen K, Kinzel B, Ludwig MG, Wells JA, Christie IN, Koolen L, Abdala AP, Liu BH, Gourine AV, Teschemacher AG, Kasparov S. CNS distribution, signalling properties and central effects of G-protein coupled receptor 4. Neuropharmacology. 2018 Aug;138:381-392. doi: 10.1016/j.neuropharm.2018.06.007. Epub 2018 Jun 9. PMID: 29894771; PMCID: PMC6063991. 2. Velcicky J, Miltz W, Oberhauser B, Orain D, Vaupel A, Weigand K, Dawson King J, Littlewood-Evans A, Nash M, Feifel R, Loetscher P. Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis. J Med Chem. 2017 May 11;60(9):3672-3683. doi: 10.1021/acs.jmedchem.6b01703. Epub 2017 Apr 26. PMID: 28445047. |
1: Liu H, Liu Y, Chen B. Antagonism of GPR4 with NE 52-QQ57 and the Suppression of AGE-Induced Degradation of Type II Collagen in Human Chondrocytes. Chem Res Toxicol. 2020 May 18. doi: 10.1021/acs.chemrestox.0c00111. Epub ahead of print. PMID: 32370492.
2: Hosford PS, Mosienko V, Kishi K, Jurisic G, Seuwen K, Kinzel B, Ludwig MG, Wells JA, Christie IN, Koolen L, Abdala AP, Liu BH, Gourine AV, Teschemacher AG, Kasparov S. CNS distribution, signalling properties and central effects of G-protein coupled receptor 4. Neuropharmacology. 2018 Aug;138:381-392. doi: 10.1016/j.neuropharm.2018.06.007. Epub 2018 Jun 9. PMID: 29894771; PMCID: PMC6063991.
