Discovery of Potent, Nonsteroidal, and Highly Selective Glucocorticoid Receptor Antagonists

Abstract

An approach to the computer-assisted, pharmacophore design of nonsteroidal templates for the glucocorticoid receptor (GR) that contained an element of pseudo-C2 symmetry was developed. The enatiomer of the initial design, 1Ra, and not the designed molecule, 1S, showed the desired ligand binding to the GR. The pseudo-C2 symmetry of the template allowed for rapid improvements in GR activity resulting in potent, selective, nonsteroidal GR antagonists, CP-394531 and CP-409069.

Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism

“…Finally, the recent disclosure by other members of the pharmaceutical industry of functional and selective GRs (sGRMs) provides additional evidence that novel NSGCAs can be obtained [20][21][22]. Hence, the NSGCAs described here, should stimulate further efforts to explore the potential for NSGCAs to lower plasma glucose levels and protein catabolism in vivo.…”

Adrenal corticosteroids, their receptors and hypertension

“…However, due to its stimulatory effect on the HPA axis, crossover to PR, and long half life, chronic usage is limited [Bamberger and Chrousos, 1995]. Non-steroidal GR antagonists have been identified [Betageri et al, 2005;Miner et al, 2003;Morgan et al, 2002]. However, pharmacological studies in animal models or clinical settings are not reported.…”

Classification and comparison of ligand-binding sites derived from grid-mapped knowledge-based potentials

“…A detailed pairwise comparison is presented for the progesterone and androgen receptor, whose binding sites are very similar. High selectivity for only one of the closely related androgen, progesterone, glucocorticoid or mineralocorticoid receptors is important in order to reduce side effects of drug candidates [23,24].…”