WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 555898
CAS#: 1950569-11-5 (HCl)
Description: EST64454 is a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management. EST64454 shows an outstanding aqueous solubility, which together with its high permeability in Caco-2 cells will allow its classification as a BCS class I compound. It also shows high metabolic stability in all species, linked to an adequate pharmacokinetic profile in rodents, and antinociceptive properties in the capsaicin and partial sciatic nerve ligation models in mice.
MedKoo Cat#: 555898
Name: EST64454 HCl
CAS#: 1950569-11-5 (HCl)
Chemical Formula: C18H23ClF2N4O2
Exact Mass:
Molecular Weight: 400.8548
Elemental Analysis: C, 53.93; H, 5.78; Cl, 8.84; F, 9.48; N, 13.98; O, 7.98
Related CAS #: 1351438-26-0 (free base) 1950569-11-5 (HCl)
Synonym: EST64454 HCl; EST64454 hydrochloride; EST64454; EST-64454; EST 64454;
IUPAC/Chemical Name: 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethan-1-one hydrochloride
InChi Key: YJZGDOPAALDWAT-UHFFFAOYSA-N
InChi Code: InChI=1S/C18H22F2N4O2.ClH/c1-14(25)23-8-6-22(7-9-23)10-11-26-13-15-4-5-24(21-15)16-2-3-17(19)18(20)12-16;/h2-5,12H,6-11,13H2,1H3;1H
SMILES Code: CC(N1CCN(CCOCC2=NN(C3=CC=C(F)C(F)=C3)C=C2)CC1)=O.[H]Cl
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: >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
| Biological target: | EST64454 hydrochloride is a selective and orally active sigma-1 receptor antagonist with a Ki of 22 nM. |
| In vitro activity: | EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug-drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. EST64454 showed a low potential for CYP inhibition (IC50 between 100 and 1000 µM) and as time-dependent inhibitor (IC50 shift mainly around 1). CYP induction studies with HepaRG™ cells revealed no CYP induction at concentrations ≤50 µM, as shown by the CYP1A2, 3A4 and 2B6 activities measured. EST64454 was not a P-glycoprotein (P-gp) substrate and was highly permeable in Caco-2 cells. Reference: Biol Pharm Bull. 2020;43(1):68-76. https://pubmed.ncbi.nlm.nih.gov/31902934/ |
| In vivo activity: | The compound 9k (EST64454) showed in vivo efficacy after oral administration in two different pain models in mice: intraplantar capsaicin-induced mechanical hypersensitivity and partial sciatic nerve ligation (PSNL)-induced mechanical hypersensitivity, a model representative of neuropathic pain. In the capsaicin test, the antiallodynic potency of 9k was similar to that of the compound 1 (ED50 33 vs 28 mg/kg, respectively, Figure 3, Table 2). In the PSNL model, oral administration of 9k at 80 mg/kg, revealed an increased antiallodynic efficacy when comparing with the same dose of the compound 1 (95% vs 54%, respectively). Reference: J Med Chem. 2020 Dec 10;63(23):14979-14988. https://pubmed.ncbi.nlm.nih.gov/31902934/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 100.0 | 249.47 |
The following data is based on the product molecular weight 400.8548 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. Díaz JL, García M, Torrens A, Caamaño AM, Enjo J, Sicre C, Lorente A, Port A, Montero A, Yeste S, Álvarez I, Martín M, Maldonado R, de la Puente B, Vidal-Torres A, Cendán CM, Vela JM, Almansa C. EST64454: a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management. J Med Chem. 2020 Dec 10;63(23):14979-14988. doi: 10.1021/acs.jmedchem.0c01575. Epub 2020 Nov 25. PMID: 33237785. 2. Yeste S, Reinoso RF, Ayet E, Pretel MJ, Balada A, Serafini MT. Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug-Drug Interactions. Biol Pharm Bull. 2020;43(1):68-76. doi: 10.1248/bpb.b19-00542. PMID: 31902934. |
| In vitro protocol: | 1. Yeste S, Reinoso RF, Ayet E, Pretel MJ, Balada A, Serafini MT. Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug-Drug Interactions. Biol Pharm Bull. 2020;43(1):68-76. doi: 10.1248/bpb.b19-00542. PMID: 31902934. |
| In vivo protocol: | 1. Díaz JL, García M, Torrens A, Caamaño AM, Enjo J, Sicre C, Lorente A, Port A, Montero A, Yeste S, Álvarez I, Martín M, Maldonado R, de la Puente B, Vidal-Torres A, Cendán CM, Vela JM, Almansa C. EST64454: a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management. J Med Chem. 2020 Dec 10;63(23):14979-14988. doi: 10.1021/acs.jmedchem.0c01575. Epub 2020 Nov 25. PMID: 33237785. |
1: Díaz JL, García M, Torrens A, Caamaño AM, Enjo J, Sicre C, Lorente A, Port A, Montero A, Yeste S, Álvarez I, Martín M, Maldonado R, de laPuente B, Vidal- Torres A, Cendán CM, Vela JM, Almansa C. EST64454: a Highly Soluble σ1 Receptor Antagonist Clinical Candidate for Pain Management. J Med Chem. 2020 Dec 10;63(23):14979-14988. doi: 10.1021/acs.jmedchem.0c01575. Epub 2020 Nov 25. PMID: 33237785.
2: Yeste S, Reinoso RF, Ayet E, Pretel MJ, Balada A, Serafini MT. Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug-Drug Interactions. Biol Pharm Bull. 2020;43(1):68-76. doi: 10.1248/bpb.b19-00542. PMID: 31902934.
