Topical corticosteroids, structure-activity and the glucocorticoid receptor: discovery and development--a process of "planned serendipity".

This is a personal recounting of the way in which the original steroid chemists and biologists worked closely together, often by trial and error, to use cortisol as the template to develop increasingly improved systemic glucocorticoids. In doing this, they learned how certain chemical functional groups affected efficacy and safety negatively and positively. When the more promising systemic glucocorticoids were subsequently applied topically, the skin barrier impaired their activity. This led to new research, this time employing in vitro percutaneous absorption evaluations coupled with in vivo vasoconstrictor studies, to screen and develop effective new topical delivery systems. A subsequent stage of this glucocorticoid research revealed that these molecules had to "fit" into receptor sites and the approximate spatial structure of such receptor sites. It also disclosed the way that the various chemical functional groups affected that "fit" and the resulting effect upon safety and efficacy.