Triamcinolone Acetonide 21-Oic Acid Methyl Ester: A Potent Local Antiinflammatory Steroid without Detectable Systemic Effects*

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Abstract
Esters of the 21-oic acid of triamcinolone acetonide (TA, 9.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxy-pregna-1,4-diene-3,20-dione 16,17-acetonide), a potent synthetic glucocorticoid, were synthesized in both tritiated and unlabeled forms. The synthesis involves oxidation to the 21-dehydro compound with methanolic cupric acetate, further oxidation to the acid with methylene blue in the presence of KCN at pH 6.5, esterification with diazomethane in the presence of methanol or ethanol, to produce the methyl ester of TA (TAme) or ethyl ester, respectively, and purification of the products by TLC and HPLC [high performance liquid chromatography]. The MW and structures of the esters were established by mass spectrometry and nuclear magnetic resonance. The binding of [3H]TAme to steroid receptors or serum steroid-binding proteins and the in vitro hydrolysis of the ester were evaluated simultaneously, by chromatography on Sephadex LH-20 columns in aqueous buffer. [3H]TAme is bound with high affinity by receptors from human leukemic cells and rat liver. The pattern of competition for this binding is characteristic of glucocorticoid receptors: TA .apprxeq. TAme > R5020 (a synthetic progestin) .apprxeq. aldosterone > 5.alpha.-dihydrotestosterone. [3H]TAme is not bound detectably by serum steroid-binding proteins and is rapidly hydrolyzed during incubation with serum at 37.degree. C. The acidic product has a very low affinity for the glucocorticoid receptor. Complexes of [3H]TAme with human and rat receptors have sedimentation coefficients of 9-10 S in hypotonic buffer containing 20 mM Na2MoO4 and .apprx. 4S in hypertonic, molybdate-free buffer. These values of sedimentation coefficient are similar to those of the oligomeric and monomeric forms, respectively, of the same receptors labeled with [3H]TA, and of mammalian steroid receptors, in general. The antiinflammatory activity of TAme in rats is comparable to that of prednisolone, but the ester is devoid of the side effects associated with prednisolone treatment (suppression of thymic weight and of serum corticosterone concentration). Thus, TAme may eventually be useful clinically, as a local antiinflammatory drug.