I. A Structure-Based Approach Toward the Development of a Ligand-Receptor System With Unique Specificity. II. Synthesis and Evaluation of Hexahydrochrysene and Tetrahydrobenzofluorene Derivatives as Selective Estrogen Receptor Modulators

Abstract

The widespread action of estrogens in the human body has prompted the development of a large variety of steroidal and non-steroidal ligands, trying to mimick or antagonize estrogenic effects. Partial agonists, with a tissue selective agonist/antagonist profile, termed selective estrogen receptor modulators (SERMs), are better candidates for applications in the treatment of estrogen sensitive breast cancer and pathologies associated with postmenopausal conditions. The basis of SERMs tissue selectivity is not clear, and possibly due to different distribution of coregulators and target gene, as well as to a different tissue distribution of the two ER receptor subtypes (ERalpha and ERbeta). Ligands in the tetrahydrobenzo[a]fluorene and hexahydrochrysene series were synthesized and evaluated for their selectivity for the two ER subtypes. Starting from those molecular scaffolds we wanted to assess the possibility of switching their effects to a SERM profile by the addition of a phenoxyethoxy-piperidinyl substituent, while conserving their receptor selectivity.