Development of G Protein‐Coupled Estrogen Receptor (GPER) Ligands for Improved Efficacy and Aqueous Solubility

Abstract

The G‐protein estrogen receptor (GPER) has been implicated in a variety of disease states and conditions. Previously our group identified a novel GPER antagonist, CIMBA, that showed improved potency as compared to the G‐series antagonist, G‐36, and exhibited the ability to reduce the formation of gallstone in a murine model. Additional modifications were made to the CIMBA scaffold to improve potency and enhance solubility. In this study, particular emphasis was placed on examining the replacement of the cyclohexyl moiety in CIMBA. Groups explored included various cyclic aliphatic systems, aliphatic chains, conjugated ring systems, piperazine, piperidine, and morpholine. Additional modifications explored the tolerance of the additional groups at the methoxy of CIMBA as well as linker modifications. Compounds were initially screened for calcium mobilization at 10 mM. All compounds exhibiting either agonism or antagonism at 10 mM were screened further to determine the appropriate EC50 or IC50 values. In this series of compounds, it was determined that the absence of the amine in the linker was detrimental to activity. Additionally, the replacement of the cyclohexyl ring in CIMBA with a piperazine (referred to as PIMBA), showed improved aqueous solubility above 10 mM without effecting the potency drastically. Off‐target binding to the nuclear estrogen receptors, ERa and ERb, was determined with a fluorescence polarization. The improved solubility of PIMBA may increase the success of in vivo studies utilizing GPER‐specific ligands in understanding the pharmacology of the receptor in different disease states.