Vol. 303, Issue 1, 196-203, October 2002

Pharmacological Actions of a Novel, Potent, Tissue-Selective Benzopyran Estrogen

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 identified a new benzopyran derivative, 3-(4-methoxy) phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-2H-1-benzopyran-7-ol hydrochloride (CHF 4227), with improved in vivo estrogen agonist/antagonist effects. CHF 4227 binds with high affinity to the human estrogen receptor- and - (dissociation constant K_i = 0.017 and 0.099 nM, respectively). In immature rats, oral administration of CHF 4227 for 3 days inhibited the uterotrophic action of 17-ethynyl estradiol (EE2) (ED₅₀ = 0.016 mg/kg · day); raloxifene was 25 times less potent as estrogen antagonist (ED₅₀ = 0.39 mg/kg · day), whereas both compounds were found to be devoid of uterotrophic activity. In line with its estrogen antagonist effect, CHF 4227 significantly prevented the development of dimethylbenz[a]anthracene (DMBA)-induced mammary tumors, the incidence being reduced from 87.5 to 26.3% 6 months after DMBA administration. In ovariectomized (OVX) rats treated orally for 4 weeks, CHF 4227 completely inhibited OVX effects on bone density (ED₅₀ = 0.003 mg/kg · day) and on serum osteocalcin levels. The protective effects on bone were comparable with those achieved with EE2, whereas raloxifene was less efficacious and 100 times less potent. CHF 4227 reduced serum cholesterol (ED₅₀ = 0.007 mg/kg · day) and had little to no stimulatory effects on uterine weight, uterine peroxidase activity, and endometrium epithelial thickness. In conclusion, CHF 4227 compares favorably in efficacy and potency with raloxifene in preventing bone loss and in antagonizing EE2 stimulation of the uterus. This profile along with the minimal uterine stimulation suggests a therapeutic advantage to CHF 4227 over EE2 or raloxifene for the treatment of postmenopausal women.