Vol. 300, Issue 3, 802-809, March 2002

Effects of 3-Phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]- 2H-1-benzopyran-7-ol (CHF 4056), a Novel Nonsteroidal Estrogen Agonist/Antagonist, on Reproductive and Nonreproductive Tissue

Elisabetta Galbiati, Paola Lorenza Caruso, Gabriele Amari, Elisabetta Armani, Silvia Ghirardi, Maurizio Delcanale and Maurizio Civelli

Departments of Pharmacology (E.G., P.L.C., M.C.) and Chemistry (G.A., E.A., S.G., M.D.), Chiesi Pharmaceuticals S.p.A., Parma, Italy

We have discovered a new, nonsteroidal, estrogen agonist/antagonist, 3-phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl] methyl]-2H-1-benzopyran-7-ol (CHF 4056). The aim of this study was to determine the effects of CHF 4056 on a series of parameters (body weight, uteri, serum cholesterol, and bones) that were previously shown to be sensitive to estrogens and to selective estrogen receptor modulators (SERMs). CHF 4056 is a benzopyran derivative that binds with high affinity to the human estrogen receptors  and  (dissociation constant K_i of 0.041 and 0.157 nM, respectively). In immature rats, CHF 4056 induced a full estrogen antagonism (half-maximal efficacious dose = 0.33 mg/kg·day p.o.) coupled with a lack of uterine stimulatory activity, whereas the structurally related SERM levormeloxifene demonstrated a maximal partial agonist effect of ~65% that of 17-ethynyl estradiol (EE2). In ovariectomized (OVX) rats, CHF 4056 (0.1-1 mg/kg·day p.o. for 4 weeks) significantly reduced OVX-induced bone loss in the lumbar spine L1-4 and OVX-induced increase in serum osteocalcin. These protective effects on bone tissue were comparable with those of 0.1 mg/kg·day EE2. In the same experimental conditions, serum cholesterol was significantly lower in the CHF 4056-treated animals, compared with vehicle-treated OVX rats. In line with the results observed in immature rats, also in OVX rats CHF 4056 diverged dramatically from EE2 and levormeloxifene in its lack of significant estrogenic effects on uterine tissue. In conclusion, CHF 4056 is a new SERM that produces beneficial effects on bone and cholesterol levels, while maintaining antagonist effects on the uterus.