Receptor binding affinity and antiproliferative activity of new antiinflammatory antedrugs: 6-methoxycarbonyl prednisolone and its derivatives.

Systemic side effects of antiinflammatory steroids may be minimized by incorporation of a metabolically labile group which is metabolized to make the steroid inactive upon entry into the systemic circulation (antedrug concept). In continuing efforts to minimize systemic adverse effects of potent antiinflammatory steroids, we have recently synthesized methyl 11 beta, 17 alpha, 21-trihydroxy-3,20-dioxopregna-1,4-diene-6-carboxylate (P6CM), its 21-acetoxys (P6CMa, P6CMb) and 17,21-acetonide (P6CMacet) derivatives. Structure-activity relationships have now been assessed and compared with prednisolone (P) for glucocorticoid receptor affinity (P IC50 = 28 nM), gluconeogenic activity as induction of tyrosine aminotransferase (EC50 = 4.4 nM) in H4-II-C3 HTC cells and antiproliferative effects (P = 48% inhibition of [3H]thymidine incorporation at 1 microM). Relative potencies for receptor binding (P = 1) were 0.12, 0.03, 0.004, and 0.0008 for P6CM, P6CMa, P6CMb, and P6CMacet, respectively, and enzyme induction relative potencies were 0.13, 0.05, 0.01, and 0.008, respectively. Antiproliferative effects of all derivatives were also less than that of P. These decreases suggest that addition of the 6-carboxymethyl group to prednisolone results in the general reduction of glucocorticoid activities. Taken together with previously reported results demonstrating retention of topical antiinflammatory activity of these novel steroids, P6CM and its derivatives may represent new locally active antiinflammatory steroids with reduced propensity to cause gluconeogenic and antiproliferative adverse effects.