Synthesis of nitro esters of prednisolone, new compounds combining pharmacological properties of both glucocorticoids and nitric oxide.
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.
Baraldi
Pier Giovanni
PG
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. pgb@ifeuniv.unife.it
Romagnoli
Romeo
R
Del Carmen Nuñez
Maria
M
Perretti
Mauro
M
Paul-Clark
Mark J
MJ
Ferrario
Massimiliano
M
Govoni
Mirco
M
Benedini
Francesca
F
Ongini
Ennio
E
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
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