Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors

Eugenia Cifuentes-Pagano; Jaideep Saha; Gábor Csányi; Imad Al Ghouleh; Sanghamitra Sahoo; Andrés Rodríguez; Peter Wipf; Patrick J Pagano; Erin M Skoda

doi:10.1039/C3MD00061C

Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors

Medchemcomm. 2013 Jul;4(7):1085-1092. doi: 10.1039/C3MD00061C.

Authors

Eugenia Cifuentes-Pagano¹, Jaideep Saha², Gábor Csányi¹, Imad Al Ghouleh¹, Sanghamitra Sahoo¹, Andrés Rodríguez¹, Peter Wipf³, Patrick J Pagano⁴, Erin M Skoda⁵

Affiliations

¹ Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
² Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA ; Center for Chemical Methodologies and Library Development, Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15261, USA.
³ Center for Chemical Methodologies and Library Development, Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15261, USA ; Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁴ Vascular Medicine Institute, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA ; pagano@pitt.edu.
⁵ Center for Chemical Methodologies and Library Development, Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15261, USA ; emf53@pitt.edu.

Abstract

(1SR,4RS)-3,3-Dimethyl-1,2,3,4-tetrahydro-1,4-(epiminomethano)naphthalenes were synthesized in 2-3 steps from commercially available materials and assessed for specificity and effectiveness across a range of Nox isoforms. The N-pentyl and N-methylenethiophene substituted analogs 11g and 11h emerged as selective Nox2 inhibitors with cellular IC₅₀ values of 20 and 32 μM, respectively.

Abstract

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