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-alpha and -beta (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 17alpha-ethynyl
estradiol (EE2) (ED(50) = 0.016 mg/kg. day);
raloxifene was 25 times less potent as
estrogen antagonist (ED(50) = 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 (ED(50) = 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 (ED(50) = 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.