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

Peter Buchwald, Nicholas Bodor

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 17α or 17β pharmacophores. For soft steroids that satisfy the main binding criteria at the glucocorticoid receptor, an indicator variable for a structural element (6α- or 9α-halogenation) and a physicochemical parameter (lipophilicity as measured by log PO/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 6α or 9α-halogenation and it also tends to increase with increasing lipophilicity.

Original languageEnglish
Pages (from-to)396-404
Number of pages9
JournalPharmazie
Volume59
Issue number5
StatePublished - May 1 2004
Externally publishedYes

Fingerprint

Glucocorticoid Receptors
Halogenation
Glucocorticoids
Adrenal Cortex Hormones
Quantitative Structure-Activity Relationship
Steroid Receptors
Drug Design
Substitution reactions
Steroids
Regression Analysis
Tissue
Chemical analysis
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Soft glucocorticoid design : Structural elements and physicochemical parameters determining receptor-binding affinity. / Buchwald, Peter; Bodor, Nicholas.

In: Pharmazie, Vol. 59, No. 5, 01.05.2004, p. 396-404.

Research output: Contribution to journalArticle

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