biostudies-literatureMazaleuskaya LLNational Center for Advancing Translational SciencesInstitute for Translational Medicine and TherapeuticsNCATS NIH HHSNHLBI NIH HHSNational Institutes of HealthPerelman School of Medicine, University of Pennsylvania128313https://www.ebi.ac.uk/biostudies/studies/S-EPMC8484072biostudies-literatureUnknown50Activated macrophages overexpress the folate receptor β (FR-β) that can be used for targeted delivery of drugs conjugated to folic acid. FR-expressing macrophages contribute to arthritis progression by secreting prostaglandin E₂ (PGE₂). Non-steroidal anti-inflammatory drugs (NSAIDs) block PGs and thromboxane by inhibiting the cyclooxygenase (COX) enzymes and are used for chronic pain and inflammation despite their well-known toxicity. New NSAIDs target an enzyme downstream of COXs, microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of mPGES-1 in inflammatory macrophages promises to retain NSAID efficacy while limiting toxicity. We conjugated a potent mPGES-1 inhibitor, MK-7285, to folate, but the construct released the drug inefficiently. Folate conjugation tBioorganic & medicinal chemistry lettersTargeted delivery of mPGES-1 inhibitors to macrophages via the folate receptor-β for inflammatory pain.PMC8484072U54 HL117798HL117798UL1TR001878UL1 TR001878Lee SMazaleuskaya LLWinkler JDFitzGerald GAMeng HfalseTargeted delivery of mPGES-1 inhibitors to macrophages via the folate receptor-β for inflammatory pain.Activated macrophages overexpress the folate receptor β (FR-β) that can be used for targeted delivery of drugs conjugated to folic acid. FR-expressing macrophages contribute to arthritis progression by secreting prostaglandin E₂ (PGE₂). Non-steroidal anti-inflammatory drugs (NSAIDs) block PGs and thromboxane by inhibiting the cyclooxygenase (COX) enzymes and are used for chronic pain and inflammation despite their well-known toxicity. New NSAIDs target an enzyme downstream of COXs, microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of mPGES-1 in inflammatory macrophages promises to retain NSAID efficacy while limiting toxicity. We conjugated a potent mPGES-1 inhibitor, MK-7285, to folate, but the construct released the drug inefficiently. Folate conjugation t2021-01-01T00:00:00Z2021 Oct2025-04-22T12:09:50.855Z2025-04-06T00:12:58.254ZS-EPMC84840723439082710.1016/j.bmcl.2021.128313