Soft glucocorticoid design: structural elements and physicochemical parameters determining receptor-binding affinity.

Following rational, retrometabolism-based drug design strategies, already two generations of cortienic acid-based soft corticosteroids have been designed. During their development, a large number of receptor-binding affinity (RBA) data for the glucocorticoid receptor (GR) were determined. RBA is a major determinant of therapeutic potential for corticosteroids, because GRs from different tissues and even from different species seem to be essentially the same. A quantitative analysis of these RBA data obtained from more than sixty structures was performed. Within both generations of soft steroids, good receptor-binding affinity could be achieved with adequate substitution at the sensitive 17alpha or 17beta pharmacophores. For soft steroids that satisfy the main binding criteria at the glucocorticoid receptor, an indicator variable for a structural element (6alpha- or 9alpha-halogenation) and a physicochemical parameter (lipophilicity as measured by log P(o/w)) account for a large portion of the variability in RBA. Following a classical, regression-type analysis, a QSAR model that accounts for close to 80% of the variability in the log RBA data could be built using only these two descriptors. According to these data, receptor binding affinity at the GR is dramatically increased by 6alpha- or 9alpha-halogenation and it also tends to increase with increasing lipophilicity.