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Vidal-Torres, AlbaAuthor

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July 8, 2021
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EST64454: a Highly Soluble sigma(1) Receptor Antagonist Clinical Candidate for Pain Management

Publicated to: Journal Of Medicinal Chemistry. 63 (23): 14979-14988 - 2020-12-10 63(23), DOI: 10.1021/acs.jmedchem.0c01575

Authors:

Luis Diaz, Jose; Garcia, Monica; Torrens, Antoni; Maria Caamano, Ana; Enjo, Juan; Sicre, Cristina; Lorente, Adriana; Port, Adriana; Montero, Ana; Yeste, Sandra; Alvarez, Ines; Martin, Miquel; Maldonado, Rafael; de laPuente, Beatriz; Vidal-Torres, Alba; Miguel Cendan, Cruz; Miguel Vela, Jose; Almansa, Carmen
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Affiliations

ESTEVE Pharmaceut, Barcelona 08038, Spain - Author
Galchimia SA, O Pino 15823, A Coruna, Spain - Author
Univ Granada, Fac Med, Dept Pharmacol, Granada 18016, Spain - Author
Univ Pompeu Fabra, Fac Ciencies Salut & Vida, Lab Neuropharmacol, Barcelona 08003, Spain - Author
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Abstract

The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone (9k, EST64454) as a sigma(1) receptor (sigma R-1) antagonist clinical candidate for the treatment of pain are reported. The compound 9k is easily obtained through a five-step synthesis suitable for the production scale and 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.
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Keywords

1 [2 [[1 (3,4 dichlorophenyl) 5 methyl 1h pyrazol 3 yl]methoxy]ethyl]piperazine1 [4 [2 [[1 (3,4 difluorophenyl) 1h pyrazol 3 yl]methoxy]ethyl]piperazin 1 yl]ethanone1 [4 [3 [[1 (3,4 dichlorophenyl) 5 methyl 1h pyrazol 3 yl]methoxy]propyl]piperazin 1 yl]ethanone4 [2 [[1 (3,4 dichlorophenyl) 5 methyl 1h pyrazol 3 yl]methoxy]ethyl]morpholine4 [3 [1 (3,4 dichlorophenyl) 5 methyl 1h pyrazol 3 yl]propyl]morpholineAnalgesiaAnalgesic activityAnalgesic agentAnalgesicsAnimalAnimal cellAnimal experimentAnimal modelAnimal tissueAnimalsArea under the curveArticleBinding affinityBiological evaluationCaco-2 cell lineCaco-2 cellsCapsaicinCarcinogenicityCell membrane permeabilityChemical structureCloningControlled studyDrug bioavailabilityDrug clearanceDrug selectivityDrug solubilityDrug stabilityDrug synthesisE 52862EmbryoEst 64454Est64454ExpressionGuidelinesHalf life timeHumanHuman cellHumansIc50IdentificationIn vitro studyIn vivo studyLigandsMaleMaximum concentrationMaximum plasma concentrationMechanical hyperalgesiaMetabolic stabilityMiceMolecular structureMouseNonhumanOpiate antagonistPainPartial sciatic nerve ligation injuryPiperazine derivativePiperazinesPlasma clearancePotassium channel hergPyrazole derivativePyrazolesRadioassayRatRats, wistarReceptors, sigmaSeriesSigma 1 opiate receptorSigma opiate receptorSigma-1 receptorSolubilityStructure activity relationStructure-activity relationshipSynthesisUnclassified drugVolume of distribution at steady-stateWistar rat

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Medicinal Chemistry due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 3/62, thus managing to position itself as a Q1 (Primer Cuartil), in the category Chemistry, Medicinal. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-12-31:

  • WoS: 14
  • Scopus: 12
  • Europe PMC: 8
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-12-31:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 19.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 20 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 7.
  • The number of mentions on the social network X (formerly Twitter): 9 (Altmetric).
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Granada.

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Awards linked to the item

We thank Ma Magdalena Bordas, Raquel Enrech, Joan Andreu Morato, Monica Carro, Edmundo Ortega, Manel Merlos, Pilar Perez, Javier Burgueno, Marta Pujol, Enrique Hernandez, Javier Farre, Eva Ayet, Raquel Fernandez-Reinoso, Maria Teresa Serafini, Carmen Segales, Alicia Pardo, Daniel Zamanillo, and Lucia Romero for their expert contribution to analytical, in vitro, and in vivo studies and Carlos Perez and Eduardo Villarroel for their contribution to compound management. This work was a part of activities in R&D Projects IDI-20110577 and IDI-20130942 supported by the Spanish Ministerio de Economia y Competitividad (MINECO), through the Centro para el Desarrollo Tecnologico Industrial (CDTI), cofinanced by the European Union through the European Regional Development Fund (ERDF; Fondo Europeo de Desarrollo Regional, FEDER).
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