title: 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.
abstract: 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 alpha and beta (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 x day p.o.) coupled with a lack of uterine stimulatory activity, whereas the structurally related SERM levormeloxifene demonstrated a maximal partial agonist effect of approximately 65% that of 17alpha-ethynyl estradiol (EE2). In ovariectomized (OVX) rats, CHF 4056 (0.1-1 mg/kg x 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 x 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.
authors.affiliation: Department of Pharmacology, Chiesi Pharmaceuticals S.p.A., Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Galbiati
authors.forename: Paola Lorenza
authors.initials: PL
authors.lastname: Caruso
authors.forename: Gabriele
authors.initials: G
authors.lastname: Amari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Armani
authors.forename: Silvia
authors.initials: S
authors.lastname: Ghirardi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Delcanale
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D015519:Bone Density / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047209:Eosinophil Peroxidase; D045166:Estradiol Congeners / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D010052:Ovariectomy; D010544:Peroxidases / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D001578:Benzopyrans; C450419:CHF 4056; D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010880:Piperidines; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D004997:Ethinyl Estradiol; C108255:levormeloxifene; D002784:Cholesterol; D047209:Eosinophil Peroxidase; D010544:Peroxidases