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

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

doi:10.1124/jpet.102.038034

Cited by 12 publications

(21 citation statements)

References 38 publications

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“…(4). Compared with raloxifene, CHF4227 binds to ERα and ERβ with higher affinity and inhibits the uterotropic action of 17alpha-ethynyl estradiol with more potency [184]. CHF4227 significantly prevents the development of DMBA-induced mammary tumors in rats [184].…”

Section: New Sermsmentioning

confidence: 99%

“…Compared with raloxifene, CHF4227 binds to ERα and ERβ with higher affinity and inhibits the uterotropic action of 17alpha-ethynyl estradiol with more potency [184]. CHF4227 significantly prevents the development of DMBA-induced mammary tumors in rats [184]. It preserves bone mass without affecting uterine weight and decreases serum cholesterol and fat mass in ovariectomized rats [185].…”

Section: New Sermsmentioning

confidence: 99%

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Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Peng¹,

Sengupta²,

Jordan

2009

ACAMC

130

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Estrogen plays vital roles in human health and diseases. Estrogen mediates its actions almost entirely by binding to estrogen receptors (ER), alpha and beta which further function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by series of experiments in the laboratory which laid the foundation of its clinical use. Unfortunately, use of tamoxifen is associated with de-novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to precisely understand the mechanism of SERM action which may further help in designing new and improved SERMs. Recent clinical studies reveal that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which not only can be used for therapeutic and preventive purposes of breast cancers but also for various other diseases and disorders. Major efforts are therefore directed to make new SERMs with a better therapeutic profile and fewer side effects.

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Section: New Sermsmentioning

confidence: 99%

Section: New Sermsmentioning

confidence: 99%

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Peng¹,

Sengupta²,

Jordan

2009

ACAMC

130

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“…CHF 4227.01 is a new benzopyran derivative recently characterized as a SERM with a promising estrogen agonist/antagonist profile on bone, serum lipids, uterus, and breast (13) . In these initial pharmacologic studies, CHF 4227.01 was more potent than RLX on bone and serum lipid endpoints, and it prevented the development of chemically induced breast tumors in the rat (13) .…”

Section: Discussionmentioning

confidence: 99%

“…This was a dose‐finding, placebo‐controlled study with three active comparators. CHF 4227.01 was identified in a screening for tissue‐selective estrogenic compounds, and it was found to have a superior estrogen agonist/antagonist activity relative to RLX in bone, serum lipids, and uterine tissue (13) . CHF 4227.01, RLX, and LFX were synthesized by Chiesi Framaceutici (Parma, Italy).…”

Section: Methodsmentioning

confidence: 99%

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

Armamento-Villareal

Sheikh

Nawaz

et al. 2005

Journal of Bone and Mineral Research

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A 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 17␣-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 CT, 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.

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“…Galbiati et al [37] have identified a new benzopyran derivative, CHF 4227 (Fig. 4), with high affinity to the human ER and ER with dissociation constant of 0.017 nM and 0.099 nM, respectively.…”

Section: Benzopyranmentioning

confidence: 98%

Recent Advances in Selective Estrogen Receptor Modulators for Breast Cancer

Wang¹,

You²,

Huang³

et al. 2009

MRMC

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Estrogen has important physiological effects on the growth and function of hormone-dependent tissues, and the link between estrogen and breast cancer has been deciphered at the end of the 20(th) century. Tamoxifen, one of the first generation selective estrogen receptor modulators (SERMs), has been the gold standard of first-line therapeutic drugs for all stages of estrogen-dependent breast cancer and has been found to reduce the incidence of breast cancer in high-risk pre- and postmenopausal women. Raloxifene, a second-generation SERM, was recently approved by FDA to decrease the risk of invasive breast cancer in postmenopausal women. During these years, many other novel types of SERAMs are being studied. This review highlights their recent advances. The discovery of selective estrogen receptor alpha modulators (SERAMs) and the latest information about their clinical and preclinical trials will be introduced intensively.

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

Cited by 12 publications

References 38 publications

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

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

Recent Advances in Selective Estrogen Receptor Modulators for Breast Cancer

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