Application of (quantitative) structure-activity relationships to progestagens: from serendipity to structure-based design

Progestagens are drugs, which are widely used in hormonal contraception and in hormone-replacement therapy. Since the natural hormone, progesterone, lacks oral activity, much effort has been devoted to finding analogues with improved oral activity and, preferably, higher potency and selectivity. A crystal structure of the hormone binding domain (HBD) region of the progesterone receptor (PR) could only be obtained recently. For more than forty years the process of designing new progestagens could therefore only be guided by the knowledge of the structure of the ligand and its corresponding in vitro/in vivo activities. While in early days chemical intuition and simple statistics (structure-activity relationship - SAR) were leading the drug design process, in later days more complex statistics and visualization tools have become routinely part of quantitative structure-activity relationship (QSAR) studies. The present review aims to provide a general overview of the strategies, efforts and achievements of synthetic and computational chemists in more than forty years of development of progestagens. (C) 2000 Editions scientifiques et medicales Elsevier SAS.