title: Synthesis of nitro esters of prednisolone, new compounds combining pharmacological properties of both glucocorticoids and nitric oxide.
abstract: Glucocorticoids (GC) are widely used in therapy for their many pharmacological properties including antiinflammatory and immunosuppressive actions. However, their use over long periods is hampered by a number of severe side effects. Given the biological properties of nitric oxide (NO) and previous experience with nonsteroidal antiinflammatory agents, we synthesized new chemical entities combining both NO and GC properties. Here we report the synthesis of nitro esters of prednisolone obtained through the esterification, with different linkers, on the hydroxy group at C-21 position of the corticosteroid structure. The alkyl chain, as of the nitrooxy derivative (2), or aromatic linkers, as of o-, m-, and p-nitrooxymethylbenzoate derivatives (3-5), respectively, furnish stable compounds that release NO and inhibit the GC receptors in biological assays. To improve solubility we introduced a more water-soluble linker such as the nitrooxyalkylpiperidine or -piperazine group (6-9). Also these compounds retained properties of both NO and prednisolone. Compound 5 (NCX 1015) was selected for its better profile: enhanced antiinflammatory properties and reduced side effects compared with prednisolone. NCX 1015 is currently under preclinical development.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. pgb@ifeuniv.unife.it
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Maria
authors.initials: M
authors.lastname: Del Carmen Nuñez
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Paul-Clark
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Ferrario
authors.forename: Mirco
authors.initials: M
authors.lastname: Govoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Benedini
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004952:Esters; D005938:Glucocorticoids / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000097:blood; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000494:pharmacology; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D004952:Esters; D005938:Glucocorticoids; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D011965:Receptors, Glucocorticoid; C418962:prednisolone 21-((4'-nitrooxymethyl)benzoate); D009569:Nitric Oxide; D011239:Prednisolone