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The parmodulin NRD-21 is an allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability.
Gandhi, Disha M; Rosas, Ricardo; Greve, Eric; Kentala, Kaitlin; D-R Diby, N'Guessan; Snyder, Vladyslava A; Stephans, Allison; Yeung, Teresa H W; Subramaniam, Saravanan; DiMilo, Elliot; Kurtenbach, Khia E; Arnold, Leggy A; Weiler, Hartmut; Dockendorff, Chris.
Afiliação
  • Gandhi DM; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Rosas R; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Greve E; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Kentala K; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • D-R Diby N; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Snyder VA; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Stephans A; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Yeung THW; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Subramaniam S; Blood Research Institute, Versiti, Milwaukee, WI 53226, USA.
  • DiMilo E; Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA.
  • Kurtenbach KE; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • Arnold LA; Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA.
  • Weiler H; Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • Dockendorff C; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA. Electronic address: christopher.dockendorff@mu.edu.
Bioorg Med Chem ; 27(17): 3788-3796, 2019 09 01.
Article em En | MEDLINE | ID: mdl-31320211
ABSTRACT
Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxazóis / Transdução de Sinais / Anti-Inflamatórios não Esteroides / Receptor PAR-1 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxazóis / Transdução de Sinais / Anti-Inflamatórios não Esteroides / Receptor PAR-1 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos