Reference

Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16a,17a-acetal-substituted glucocorticoids

Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16a,17a-acetal-substituted glucocorticoids. Dahlberg, Erik; Thalen, Arne; Brattsand, Ralph; Gustafsson, Jan Aake; Johansson, Ulf; Roempke, Karin; Saartok, Tonu (Dep. Med. Nutr., Karolinska Inst., Huddinge S-141 86, Swed.). Mol. Pharmacol., 25(1), 70-8 (English) 1984. CODEN: MOPMA3. ISSN: 0026-895X. DOCUMENT TYPE: Journal CA Section: 2 (Mammalian Hormones) The affinity for the glucocorticoid receptor in rat skeletal muscle of some glucocorticoids with a new type of 16a,17a-acetal substituent was estd. and correlated to the glucocorticoid activities in 3 in vivo systems in rats. Budesonide [51333-22-3] (an approx. 1:1 mixt. of the C(22) epimers of 11b,21-dihydroxy-16a,17a-[(22R,S)-propylmethylenedioxyl]-pregna-1, 4-diene-3,20-dione) and the isolated (22R) [51372-29-3]- and (22S)-epimers [51372-28-2] bound to the same binding site as the potent glucocorticoids dexamethasone (DEX) [50-02-2] or triamcinolone 16a,17a-acetonide (TA) [76-25-5], but with even higher affinity than DEX or TA. The (22R)-epimer was twice as active as the (22S)-epimer, 4 times more active than TA, and 14 times more active than DEX. The introduction of a 9a-fluoro atom slightly decreased the binding affinity of the (22R)-epimer of budesonide, in contrast to the pos. effect of 9a-fluorination of, e.g., 16a,17a-acetonides. The neg. influence of 9a-fluorination of the (22R)-epimer was partially reversed in the 6a,9a-difluorinated (22R)-epimer [51547-52-5]. Nevertheless, the fluorinated compds. were more active than DEX and TA. Budesonide is metabolized mainly to 16a-hydroxyprednisolone [13951-70-7] and 6b-hydroxy-budesonide [88411-77-2]. Both metabolites were very weak competitors for the ligand-binding sites on the receptor. The affinity for the receptor in vitro was closely correlated to the topical glucocorticoid activity in vivo for the 12 steroids compared, which supports the contention that in vitro tests for receptor affinity are useful when screening for agonists among steroids with the present type of structures. The results on receptor-ligand interaction are in accordance with x-ray cyrstallog. data available for some steroids.

Kinetics of the epimeric glucocorticoid budesonide

Kinetics of the epimeric glucocorticoid budesonide. Ryrfeldt, Aake; Edsbaecker, Staffan; Pauwels, Romain (Res. Dev. Lab., AB Draco, Lund, Swed.). Clin. Pharmacol. Ther. (St. Louis), 35(4), 525-30 (English) 1984. CODEN: CLPTAT. ISSN: 0009-9236. DOCUMENT TYPE: Journal CA Section: 2 (Mammalian Hormones) The pharmacokinetics of 22R- [51372-29-3] and 22S-budesonide [51372-28-2], administered as a 1:1 mixt. (500 mg, i.v.), were studied in 6 healthy male subjects. Estn. of epimer concns. in blood plasma was by HPLC. The half-time for plasma elimination, distribution vol. (Vb), and plasma clearance for the 22R epimer were 2.66 h, 425 L, and 117 L/h and the corresponding values for the 22S epimer were 2.71 h, 245 L, and 67 L/h, resp. The larger Vb for the 22R epimer may be a result of higher tissue affinity. Budesonide (I) [51333-22-3] slightly decreased plasma cortisol [50-23-7] levels and had the expected glucocorticoid effects on white blood cell counts; both effects were small and transient.