There are >60 million women over age 50 in the U.S., of which more than half experience negative symptoms of menopause. Our market research indicates that major symptoms of menopause for which women desire treatment are hot flashes and memory dysfunction. While at least 70% of women suffer these symptoms during the menopausal transition, few effective treatments are available. Estrogen therapy (ET) has been the primary treatment for menopausal symptoms, with the hormone therapy market expected to reach $28 billion by 2022. However, ET is associated with increased risks of cancer and heart disease, leading many women to forgo treatment or to use ineffective or unproven alternative treatments. Not only is the lack of safe and effective treatments disruptive to women’s lives, but women whose menopausal symptoms go untreated incur greater healthcare costs, more physician visits, and lower work productivity than women who use ET or are asymptomatic. The primary culprit in the negative effects of ET is estrogen receptor alpha (ERα), one of two intracellular ERs through which estrogens affect cellular function. Whereas activation of ERα is associated with ET-induced health risks, ERβ activation benefits vasomotor function and cognition. Thus, selective activation of ERβ may reduce menopausal symptoms without incident risk of detrimental health outcomes. Estrigenix’s mission is to develop drugs to help women live healthier and longer lives. The overall objective of this proposal is to optimize and develop our lead compound, the novel ERβ agonist EGX358, as a therapeutic to treat hot flashes and memory decline in menopausal women. This research is innovative because EGX358 is the most selective ERβ agonist reported to date, and is in a unique structural class possessing a cyclohexane-based saturated ring system, substituted with a hydroxymethylene group. Our central hypothesis is that EGX358 will alleviate symptoms of menopause, including hot flashes and memory decline, in a middle-aged mouse model of menopause, and is suitable for further preclinical studies based on preliminary pharmacokinetics and process chemistry. This hypothesis is based on our studies using a young ovariectomized mouse model of menopause showing that acute and/or chronic oral EGX358 treatment alleviates drug-induced hot flashes and enhances memory formation, without affecting breast cancer cell proliferation or causing off-target effects on nuclear hormone receptor binding or tissue pathology. Our hypothesis will be tested in three specific aims designed to: 1) demonstrate that EGX358 can reduce hot flashes and enhance memory in a middle-aged mouse model of menopause, 2) demonstrate minimal toxicity and favorable pharmacokinetic (PK) stability for EGX358 (or an optimized analog), 3) develop process chemistry scaleup synthesis of EGX358 suitable for method transfer to a cGMP lab to produce sufficient material for clinical trials. This Phase II enabling work will demonstrate that EGX...