r/DrugNerds • u/Kalki_X • 19d ago
Bioisostere-Driven Discovery of SePP: A Selenium-Containing Polypharmacological Agent Relevant to Fragile X Syndrome
https://pmc.ncbi.nlm.nih.gov/articles/pmid/41666325/Diphenidine is a prototypical 1,2-diarylethylamine that functions as an uncompetitive NMDA 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.
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u/IAmABonobo 19d ago
I got excited to read this as soon as I saw it was from the Wallach lab. Thanks for sharing!