Heat maps were generated for the subset of compounds that showed consistent agreement of ER or AR binding at ToxCast™ AC 50 < 1 μM and where the QSAR models predicted in-domain binding for the parents or known hydroxylated metabolites 100% of the time. The heat maps ( Figure 2 ) show the distribution of ToxCast™ in vitro activity for each assay and are color-coded by potency. This subset of compounds was active in all ER and AR transactivation assays where metabolism was incorporated with addition of an exogenous S9 fraction (OT platform). For those compounds in this subset known to require metabolism to manifest activity, the transactivation response appears to be less promiscuous than binding because of the mixed nature of the response in these assays, which may reflect some degree of constitutive metabolism depending on cell type.
Those skilled in the art will recognize that stereocenters exist in compounds of Formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of Formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of Formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of Formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.