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**10** 

*Departments of* 

*The Netherlands* 

*2Medicinal Chemistry* 

**Drug Design Approaches to Manipulate** 

The steroid hormone receptors, the Androgen Receptor (AR), Estrogen Receptors (ERα and ERβ), Glucocorticoid Receptor (GR), Mineralocorticoid Receptor and Progesterone Receptor (PR), have been crucial targets for drug discovery even before their existence was known or understood. The drugs on the market for this sub-class of the nuclear hormone receptors constitute a significant pharmacopeia for the treatment of a vast array of conditions and ailments. Despite the breadth of drugs targeted toward this family, they remain an

Key considerations when designing drugs for any family, beyond the on-target pharmaceutical action and safety, is to ensure specificity against related targets, exploration of the most appropriate routes of administration and desirable pharmacokinetic (PK) profiles. Developing non-steroidal modulators for the steroid receptor family has been a key strategy employed to achieve these goals, although there appears to be growing consensus that not being steroidal is insufficient to justify new drugs on its own (Hermkens et al, 2006). Unlike targeting many families, steroid hormone receptor drug discovery also has to balance the need to elicit either agonistic or antagonistic responses depending on the desired

The history of drug discovery for the steroid hormone receptors has tended to follow a common path, beginning with the application of purified endogenous hormone and followed by the application of the first synthetic analogs with improved PK properties or selectivity. For some of the receptors this period was followed by the design of antagonists, including non-steroidal structures. More recently, steroid hormone drug discovery has been

**1. Introduction**

indication.

important target for the pharmaceutical industry.

**the Agonist-Antagonist Equilibrium** 

Scott J. Lusher1,6, Paolo Conti2, Wim Dokter3, Pedro H. Hermkens2,4 and Jacob de Vlieg1,5,6

**in Steroid Receptors** 

*1Molecular Design & Informatics,* 

*3Immune Therapeutics, MSD, Oss 4Institute of Molecules & Materials 5Computational Drug Discovery Group,* 

> *Radboud University, Nijmegen, 6Netherlands eScience Center,*

Based on Related Crystal Structure and Mutational and Structure-Activity Relationship Data. *J. Med. Chem.*, Vol.41, No.11, (May 1998), pp. 1803-1814, ISSN 0022-2623

