Structure-Activity Relationships in Glucocorticoids

Topical Corticosteroids, Structure-Activity and the Glucocorticoid Receptor: Discovery and Development—A Process of ‘‘Planned Serendipity’’

“…There was a slow and steady progression of “molecular acrobatics” as scientists learned how to add functional groups at various positions on the steroid molecule and gradually discerned which of these had been either beneficial or detrimental from the results of the various biological assays 10. For instance, changes that stabilized a corticoid to metabolic inactivation would enhance potency, although they might negatively affect other processes 11. Table 1 presents an approximately chronological sequence of the step‐by‐step additions of functional groups to systemic corticosteroids, resulting in improvements in biological activity.…”

“…Wolff11 studied the binding of corticoids to serum albumin and what was defined as corticoid‐binding‐globulin. He measured the effect that structural changes had on factors such as metabolism of the compound, intrinsic activity, and receptor binding affinity.…”

“…From this, he developed a mathematical model relating activity to four physical‐chemical and size parameters. He noted that “the energy of binding could best be accounted for if the entire steroid were enveloped on both sides by the receptor 11. As an analogy, the steroid appears as a ‘hamburger patty’ enveloped on both sides by the ‘hamburger bun’ of the receptor.” A more advanced version of the receptor concept, the “Glucocorticoid Receptor” is discussed below.…”

“…With the advent of molecular biology, the blueprint of the glucocorticoid receptor was elucidated 43. The concept of a “hamburger bun” or “pocket” was added to the “lock” as a potential descriptor of the “receptor.”11 It was now possible to visualize how those effective substituent functional groups of the glucocorticoid bound to specific amino acid groupings and activated the glucocorticoid receptor. The glucocorticoid receptor, in turn, bound DNA and transcribed the message to RNA, which activated gene expression that then produced the cellular results associated with glucocorticoids.…”

Studies on the Pharmacokinetics and Metabolism of Prednicarbate after Cutaneous and Oral Administration

“…On the basis of the studies on intra dermal metabolism of corticoids, it has been established for human skin that this type of esterolytic reaction occurs in the skin [Pannatier et al, 1978;Cheung et al, 1985;Tauber and Rost, 1987], Alongside enzymatic ester hydrolysis, nonenzymatic conversions, especially of C l7 monoesters, can apparently also take place in the epidermis [Bundgaard and Hansen, 1981;Yip et al, 1983]. In contrast to this, halogen substituents, most often in position Cftalpha and Gjalpha, increase the affinity of the gluco corticoid molecule to the intracellular recep tor protein and thus lead to an increase in the intrinsic activity of the steroid on the one hand; on the other hand halogen substituents cause a delay of the systemic metabolism [Myles et al, 1957;Wolff, 1979]. By means of highly potent, sometimes multiple-halogenated glucocorticoids, strong local effects can often be caused even with only small amounts of substance penetrating the deeper layers of the skin; this holds also true, however, of the amount of substance reaching the systemic circulation, which invalidates one of the es sential arguments for a purely locally oriented form of therapy.…”