2. Academic Validation
  3. Bioisostere-Driven Discovery of SePP: A Selenium-Containing Polypharmacological Agent Relevant to Fragile X Syndrome

Bioisostere-Driven Discovery of SePP: A Selenium-Containing Polypharmacological Agent Relevant to Fragile X Syndrome

  • J Med Chem. 2026 Feb 26;69(4):4020-4036. doi: 10.1021/acs.jmedchem.5c02700.
Jason Wallach 1,  Sean Cameron 1,  Michael Dybek 1,  Branden Stanley 2,  Christopher Orme 1,  Nour Riad 1,  Pierce Kavanagh 3,  Simon D Brandt 4,  Adam Knapp 1,  James Gamrat 1,  Rebekah Jauhola-Straight 1,  Adeboye Adejare 1,  Alexander J Rogier 5,  Richa Tyagi 5,  Clinton E Canal 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy. Saint Joseph's University, 600 South 43rd St., Philadelphia, Pennsylvania 19104, United States.
  • 2 Department of Chemistry, Philadelphia College of Pharmacy. Saint Joseph's University, 600 South 43rd St., Philadelphia, Pennsylvania 19104, United States.
  • 3 Discipline of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, Saint James's Hospital, Dublin, Ireland D08 W9RT.
  • 4 The Alexander Shulgin Research Institute, 1483 Shulgin Road, Lafayette, California 94549, United States.
  • 5 College of Pharmacy, Department of Pharmaceutical Sciences, Mercer University, 3001 Mercer University Drive, Atlanta, Georgia 30341, United States.
PMID: 41666325 DOI: 10.1021/acs.jmedchem.5c02700
Abstract

Diphenidine is a prototypical 1,2-diarylethylamine that functions as an uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist and monoamine reuptake inhibitor. To examine the effects of phenyl-ring bioisosteric replacement within this scaffold, a series of diphenidine analogs incorporating chalcogen heterocycles (2-furan, 2-thiophene, 3-thiophene, and 2-selenophene) was synthesized. Compounds were evaluated for in vitro binding to rat forebrain NMDARs and inhibition of human DAT, NET, and SERT in cell-based assays, enabling assessment of polypharmacology. In silico analyses (molecular volume, tPSA, electrostatic surfaces, stockholder charges) and induced-fit docking were used to rationalize structure-activity relationships. The 2-selenophene analog SePP is notable given the underexplored role of selenium in medicinal chemistry. SePP exhibited favorable polypharmacology, good brain penetration in mouse pharmacokinetic studies, and prevented audiogenic seizures in Fmr1 knockout mice (10 mg/kg, i.p.) without impairing motor coordination. These findings support further exploration of SePP for fragile X syndrome.

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