Author: Antoine Tarral ; Marie-Claude Homery ; Ivano Rondelli ; Philippe Dostert ; Daniele Guastalla ; Alessandro Piero Monici Preti ; Yann Guillevic ; Maurizio Civelli ; Valentina Cenacchi

What is already known about this subject• CHF 4227 is a selective oestrogen receptor modulator (SERM) that compares favourably in efficacy and potency with raloxifene in preventing bone loss and lowering serum cholesterol concentrations in OVX rats.• The compound prevented the development of DMBA‐induced mammary carcinoma in rats.• In preclinical studies, CHF 4227 differs from oestrogens and from others SERMs, such as levormeloxifene, in its lack of oestrogenic effects on uterine tissue.What this study adds• CHF 4227 is a well‐tolerated SERM for postmenopausal women dosed once daily for 28 days. It appears to effect beneficially bone tissue and serum lipids without inducing oestrogenic actions on the endometrium, negative effects on fibrinolytic system, and without worsening menopausal symptoms, in particular hot flushes.• CHF 4227 is a promising agent for the treatment of several conditions in postmenopausal women.AimsWe evaluated the tolerability, adverse events profile, pharmacokinetics, and pharmacodynamics of CHF 4227, a new selective oestrogen receptor modulator (SERM), in healthy postmenopausal women.MethodsTwo phase I studies were conducted according to a double‐bind, placebo‐controlled design. Subjects were randomized to receive six single (5–400 mg) or five multiple oral doses of CHF 4227 for 28 days (5–100 mg).ResultsNo vaginal bleeding and no changes in either endometrial thickness or the placenta protein 14 marker were found after 4 weeks of treatment. The compound did not induce negative effects on the fibrinolytic system. After 28 days of treatment, CHF 4227 decreased both total and LDL cholesterol concentrations (maximum decreases from baseline of 17.4% (95% CI 7.0, 27.7) and 27.6% (95% CI 9.0, 46.3), respectively). Decreases in both serum and urinary type‐I C‐terminal collagen telopeptide were also observed producing maximum changes of 40.6% (95% CI 29.5, 51.7), and 41.7% (95% CI 20.3, 56.8), respectively. CHF4227 (5 and 10 mg) induced near maximal oestrogen‐like effects on bone markers and serum lipids without causing hot flushes. The pharmacokinetics of CHF 4227 were characterized by a slow absorption, a long elimination half‐life (31–42 h after single administration) and dose linearity with respect to Cmax and AUC up to 100 mg.ConclusionsCHF 4227 is a well‐tolerated SERM when administered once daily for 28 days. It is potentially active on bone resorption and serum lipids, without affecting the endometrium and without worsening hot flushes. CHF 4227 is a promising agent for the treatment of several conditions in postmenopausal women.

01 Dec 2005·Journal of Bone and Mineral ResearchQ1 · MEDICINE

A New Selective Estrogen Receptor Modulator, CHF 4227.01, Preserves Bone Mass and Microarchitecture in Ovariectomized Rats

Q1 · MEDICINE

Article

Author: Elisabetta Galbiati ; Roberto Civitelli ; Abroo Nawaz ; Nicola Napoli ; Sharmin Sheikh ; Maurizio Civelli ; Michael D Brodt ; Linda R Halstead ; Paola Lorenza Caruso ; Cheryl Mueller ; Matthew J Silva ; Reina Armamento-Villareal

AbstractA new SERM, CHF 4227.01, given to 6-month-old female rats immediately after ovariectomy, preserved bone mass and bone microarchitecture without affecting uterus weight. It also decreased serum cholesterol and fat mass in estrogen-deficient rats.Introduction: We tested the effect of a new benzopyran derivative, CHF 4227.01, with selective estrogen receptor modulator (SERM) activity on bone mass and biomechanics in ovariectomized (OVX) female rats in comparison with 17α-ethinylestradiol (EST), raloxifene (RLX), and lasofoxifene (LFX).Materials and Methods: Four doses of CHF 4227.01 (0.001, 0.01, 0.1, and 1 mg/kg body weight [bw]/day) were administered in OVX animals daily by gavage 5 days/week for 4 months. EST was administered at a dose of 0.1 mg/kg bw/day, whereas RLX and LSX were administered at doses of 1 and 0.1 mg/kg bw/day, respectively, by gavage. In one group (Sham), rats were operated but the ovaries not removed; another OVX group was treated only with placebo.Results and Conclusions: Treatment with CHF 4227.01 (1.0 and 0.1 mg/kg bw), EST (0.1 mg/kg bw), LFX (0.1 mg/kg bw), or RLX (1.0 mg/kg bw) prevented bone loss on the lumbar spine and the proximal femur assessed in vivo by DXA. Volumetric BMD obtained by pQCT ex vivo confirmed protection from bone loss in the spine and proximal femur among rats treated with CHF 4227.01. This effect was associated with strong inhibition of bone resorption both histologically and biochemically. Furthermore, CHF 4227.01 preserved trabecular microarchitecture, analyzed by μCT, and maintained biomechanical indices of bone strength in the spine and proximal femur, effects also observed for RLX, whereas LSX was less protective of microarchitecture. CHF 4227.01 treatment did not affect uterine weight, prevented the increase in body weight and fat mass seen in OVX animals, and decreased serum cholesterol to below the average of intact animals. In conclusion, CHF 4227.01 exhibits a promising therapeutic and safety profile as a new SERM on both skeletal and extraskeletal outcomes.

01 Oct 2002·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Armani, Elisabetta ; Ghirardi, Silvia ; Caruso, Paola Lorenza ; Amari, Gabriele ; Delcanale, Maurizio ; Civelli, Maurizio ; Galbiati, Elisabetta

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.

100 Deals associated with CHF-4227

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 1	IT	CHIESI Farmaceutici SpA	-
Osteoporosis, Postmenopausal	Phase 1	IT	CHIESI Farmaceutici SpA	-

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