ChemInform Abstract: Evidence for New Non-Steroidal Human Aromatase Inhibitors and Comparison with Equine Aromatase Inhibition for an Understanding of the Mammalian Active Site.

Abstract

Abstract We developed a new comparative model in order to better understand the structure-function relationships of the active site in human aromatase. Thus, we undertook the comparative inhibition of human and equine aromatases with new compounds. In fact, equine aromatase represents the only easy and available mammalian membrane-bound enzyme model, besides the human one, which is biochemically purified, well characterized and cloned. During the course of our work concerning the synthesis and screening of new drugs on human and equine aromatases, we identified two new indane derivatives which inhibited the human enzyme (IC 50 = 3.5 μM and 5.9 μM) strongly and selectively while they were much less active on the equine one (IC 50 > 10 μM). The hitherto known aromatase inhibitors, such as 4-hydroxyandrostenedione (4-OHA) and some other indane-related derivatives, are equally efficient on both human and equine enzymes. In this work, using a theoretical 3D model of aromatase, we have explained the human selectivity of the new described compounds as due to the specific differences between the primary structure of both active sites in human and equine enzymes. These results could allow synthesis of a new family of compounds that are much more potent and selective aromatase inhibitors.