Generation of innovative anti-inflammatory and anti-arthritic glucocorticoid derivatives that release NO: the nitro-steroids.

Abstract

Addition to the prednisolone structure of a chemical moiety (linker+nitric ester) that releases NO species yielded a novel glucocorticoid (nitro-prednisolone or NCX-1015) with enhanced anti-inflammatory activities. Nitro-prednisolone was much more potent than prednisolone and the derivative devoid of the nitric ester in an acute peritonitis model (higher impact on neutrophil migration and soluble mediator generation) as well as in models of chronic inflammation (air-pouch granuloma and collagen II-induced arthritis). In the collagen II-induced arthritis model, NCX-1015 abrogated the plasma levels of a catabolite of cartilage and bone metabolism, indication of a disease modifying action. In an in vitro assay of bone resorption, NCX-1015 did not activate osteoclast activity, whereas prednisolone did. This lack of effect of NCX-1015 was chiefly due to NO. We propose that NCX-1015 is the prototype of a new class of glucocorticoids, the nitro-steroids, endowed with enhanced anti-inflammatory properties and reduced side effects. These and other experimental observations here reviewed may prompt the assessment of the clinical impact of the nitro-steroids on rheumatoid arthritis and inflammatory bowel disease.

• Authors: M Perretti, M J Paul-Clark, L Mancini, R J Flower
• Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver (Dig Liver Dis) Vol. 35 Suppl 2 Pg. S41-8 (May 2003) ISSN: 1590-8658 [Print] Netherlands
• PMID: 12846443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Anti-Inflammatory Agents
• Glucocorticoids
• Receptors, Glucocorticoid
• prednisolone 21-((4'-nitrooxymethyl)benzoate)
• Nitric Oxide
• pyridinoline
• Prednisolone

Topics

• Amino Acids (blood)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Arthritis, Experimental (drug therapy)
• Disease Models, Animal
• Glucocorticoids (pharmacology, therapeutic use)
• In Vitro Techniques
• Nitric Oxide (analogs & derivatives, therapeutic use)
• Osteoclasts (drug effects)
• Prednisolone (analogs & derivatives, pharmacology, therapeutic use)
• Rats
• Receptors, Glucocorticoid