Non-steroidal glucocorticoid-like substances: receptor binding and in vivo activity

• Published in: Journal of medicinal chemistry Vol. 36; no. 22; pp. 3278 - 3285
• Main Authors: Kumar, Virendra, Bell, Malcolm R, Wetzel, Joseph R, Herrmann, John L, McGarry, Ruthann, Schane, H. Phillip, Winneker, Richard C, Snyder, Ben W, Anzalone, Anthony J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.10.1993
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Glucocorticoids - chemical synthesis; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - metabolism; Pyrazoles - pharmacology; Rats; Receptors, Glucocorticoid - metabolism; Structure-Activity Relationship; Non steroidal antiinflammatory agent; Biological fixation; Structure activity relation; Antiinflammatory agent; Diels Alder addition; Hormonal investigation; Chemical synthesis; Glucocorticoid; Physical properties; Biological activity; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00074a008

Compounds of general structure I, prepared by a Diels-Alder reaction with diene 3, are relatives of the known potent glucocorticoid II but possess a markedly modified C- and D-ring environment. Despite these structural changes, 4, 5, 9, 10, 12a, 13, and 14 bound to the glucocorticoid receptor with an affinity which approximated that of the reference standard, 6-alpha-methylprednisolone. Four of these compounds not only exhibited antiinflammatory activity in the alpha-tocopherol pouch test but also exhibited marked adrenal suppression and other typical glucocorticoid properties at doses in the same range as the effective antiinflammatory doses.