Lasofoxifene
(Synonyms: 拉索昔芬; CP-336156) 目录号 : GC44036
A selective ER modulator
Cas No.:180916-16-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Lasofoxifene is a third-generation, non-steroidal selective estrogen receptor modulator (SERM). It selectively binds to human ERα with an IC50 value of 1.5 nM and inhibits bone loss in ovariectomized rats. In clinical studies of postmenopausal osteoporosis, 0.5 mg/day lasofoxifene was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. Lasofoxifene has also been shown to act as an inverse agonist at the CB2 cannabinoid receptor, indicating its potential to be repurposed as a therapeutic for indications wherein CB2 is a target.
| Cas No. | 180916-16-9 | SDF | |
| 别名 | 拉索昔芬; CP-336156 | ||
| Canonical SMILES | OC(C=C1)=CC2=C1[C@@H](C3=CC=C(OCCN4CCCC4)C=C3)[C@@H](C5=CC=CC=C5)CC2 | ||
| 分子式 | C28H31NO2 | 分子量 | 413.6 |
| 溶解度 | DMF: 20 mg/ml,DMSO: 20 mg/ml,DMSO:PBS (pH 7.2) (1:1): 0.5 mg/ml,Ethanol: 1.5 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4178 mL | 12.089 mL | 24.1779 mL |
| 5 mM | 0.4836 mL | 2.4178 mL | 4.8356 mL |
| 10 mM | 0.2418 mL | 1.2089 mL | 2.4178 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Lasofoxifene in osteoporosis and its place in therapy
Adv Ther 2010 Dec;27(12):917-32.PMID:21080249DOI:10.1007/s12325-010-0081-y.
Selective estrogen-receptor modulators (SERMs), which have estrogen-like effects on bone and "antiestrogen effects" on other tissues, have been in development for osteoporosis prevention and treatment in postmenopausal women as a safer alternative to long-term estrogen. We conducted a literature review of the skeletal and extraskeletal effects of Lasofoxifene, a new generation SERM approved by the European Commission for osteoporosis treatment. Published data on the effects of Lasofoxifene are based on 23 clinical pharmacology studies with over 10,000 participants from 17 phase 2 and 3 randomized controlled trials (RCTs). In RCTs, Lasofoxifene decreases bone turnover markers (BTMs), increases bone mineral density (BMD) at the spine and hip, and decreases the incidence of vertebral and nonvertebral nonhip fractures compared with placebo. Compared with raloxifene, Lasofoxifene gave greater decreases in BTMs, and greater increases in lumbar spine BMD. Lasofoxifene also decreased the risk of breast cancer, major coronary heart disease events, and stroke, but-similar to raloxifene-there was an increased risk of venous thromboembolism. In one trial, endometrial hypertrophy and uterine polyps were more common with Lasofoxifene than with placebo, but endometrial cancer and hyperplasia were not. Lasofoxifene is probably most appropriate for use among women in their early or middle menopausal years (age 55-65) who have, or are at risk of developing, osteoporosis and in particular vertebral fractures. At the time of publication, Lasofoxifene is not approved for use by the US Food and Drug Administration, and as such is not used in North America.
Lasofoxifene: CP 336156, CP-336156
Drugs R D 2005;6(1):56-60.PMID:15801869DOI:10.2165/00126839-200506010-00008.
Lasofoxifene [CP 336156] is a potent, nonsteroidal, tissue-selective estrogen receptor modulator (SERM). It has the bone-sparing and cardioprotective effects of estrogen, but lacks estrogen's uterine cancer risk. Lasofoxifene is under development with Ligand Pharmaceuticals and Pfizer (formerly Parke-Davis) for the prevention of postmenopausal osteoporosis and breast cancer. In June 2000, Parke-Davis' parent company, Warner-Lambert, merged with Pfizer. The resulting company retained the Pfizer name and Parke-Davis was integrated into Pfizer Global Research and Development. The discovery of Lasofoxifene resulted from a research collaboration between Pfizer and Ligand Pharmaceuticals. There was a contract dispute between the two companies relating to their research agreement. Under a settlement of litigation, Ligand is entitled to milestone and royalty payments. If Pfizer is successful in developing the drug through to regulatory approval in the US, Ligand could receive royalty revenues from Lasofoxifene as early as 2003-2004. The royalties will be equal to 6% of net sales and will be in addition to milestone payments for continuing development of the drug. However, on 6 March 2002, Ligand Pharmaceutical announced an agreement with Royalty Pharma in which the latter purchased the rights to a share of these future payments. Under the agreement, Ligand received US dollars 6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (Lasofoxifene, bazedoxifene and bazedoxifene/Premarin) for a period of 10 years. Royalty Pharma retains the option to purchase, at escalating prices, additional rights (subject to timing restrictions) to extend this stake up to 1.0%, for a total of US dollars 56 million. In April 2002, Royalty Pharma exercised its first option to purchase an additional 0.125% of potential future sales of the three SERMS in exchange for US dollars 3 million. Subsequently, in December 2002, Royalty Pharma exercised an expanded option and agreed to pay Ligand US dollars 6.775 million for 0.1875% of potential future sales of SERM products. Royalty Pharma and Ligand Pharmaceutical amended their royalty agreement in October 2003 for the three SERM products. Under the amended agreement, Royalty Pharma exercised an option to pay Ligand US dollars 12.5 million, plus cumulative milestones of up to US dollars 2.5 million upon the launches of the three SERMs (provided they are approved by 30 September 2005), in exchange for 0.7% of potential future sales of the products for 10 years. In November 2004, Ligand Pharmaceuticals and Royalty Pharma further amended their existing royalty agreement for the three SERM products. Under the terms of the revised agreement, Royalty Pharma will purchase an additional 1.625% of the SERM products' net sales for US dollars 32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following the first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of Lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets will be paid to Ligand as earned and are not included in this amended agreement. In September 2004, Ligand Pharmaceuticals earned a milestone payment of approximately US dollars 2 million from Pfizer, payable in 181,818 shares of Ligand stock held by Pfizer. The payment was triggered by Pfizer's NDA submission for Lasofoxifene in August 2004. Under the terms of the agreement between Ligand and Pfizer, Ligand is entitled to receive an additional milestone upon successful approval of Lasofoxifene. On 19 August 2004, Pfizer filed an NDA with the US FDA for Lasofoxifene for the prevention of osteoporosis in postmenopausal women. Product launch is forecasted to occur in 2006-2007. Ligand reported in January 2004 at the 22nd Annual JP Morgan Healthcare Conference that it anticipated the availability of phase III data and NDA filing sometime in 2004. Lasofoxifene has undergone two phase III studies with Pfizer in the US as an orally administered therapy for postmenopausal osteoporosis. In June 2003, Pfizer reported that enrolment was completed in a trial evaluating Lasofoxifene in the prevention of bone loss. The trial also evaluated Lasofoxifene's effect on lipid levels. The trial enrolled approximately 2000 postmenopausal women. Another trial was conducted among 8500 patients to investigate Lasofoxifene in the treatment of fractures. In addition, Pfizer began a third worldwide phase III trial to evaluate whether Lasofoxifene reduced the risk of vertebral fractures, breast cancer and cardiovascular disease. At the 10th Annual Meeting of the Biotechnology Industry Organization (BIO-2003), Ligand also confirmed that Lasofoxifene was in phase III development for breast cancer. Lasofoxifene is under clinical evaluation as a treatment for vaginal atrophy. According to Pfizer's pipeline in November 2004, the company anticipates regulatory submission for vaginal atrophy by the end of 2004. In June 2002, Ligand estimated that Lasofoxifene has the potential to reach sales of US dollars 1-2 billion, pending approval.
Lasofoxifene: selective estrogen receptor modulator for the prevention and treatment of postmenopausal osteoporosis
Ann Pharmacother 2011 Apr;45(4):499-509.PMID:21467260DOI:10.1345/aph.1P604.
Objective: To review literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of Lasofoxifene (CP-336156), a selective estrogen receptor modulator (SERM) that is not approved for use in the US. Data sources: Literature was accessed through the MEDLINE and EMBASE databases (1985-June 2010) using the terms Lasofoxifene and selective estrogen receptor modulators. Reference lists from retrieved articles were also manually reviewed. The Food and Drug Administration and Pfizer provided additional information. Study selection and data extraction: All clinical trials evaluating Lasofoxifene were included in this review. In addition, all articles evaluating the pharmacology, pharmacokinetics, and safety of Lasofoxifene in humans were reviewed. Data synthesis: Lasofoxifene is a third-generation SERM with markedly higher in vitro and in vivo potency and oral bioavailability than other SERMs. The drug has produced significant improvements in bone density and biochemical markers of bone turnover in preclinical studies and in Phase 2 and 3 clinical trials. In these trials, Lasofoxifene has shown a favorable safety profile, with adverse events including hot flushes, leg cramps, and increased vaginal moisture. One 2-year major comparative study in postmenopausal women determined that Lasofoxifene and raloxifene were equally effective at increasing total hip bone mineral density (BMD), while Lasofoxifene had a significantly greater effect on lumbar spine BMD. Conclusions: Osteoporosis is a significant health problem. While the results of further clinical trials are needed to define the risks and benefits of treatment, particularly relating to fractures, Lasofoxifene may prove to be an effective and well-tolerated therapeutic option for the prevention of bone loss in postmenopausal women.
[Lasofoxifene, a next generation estrogen receptor modulator: preclinical studies]
Clin Calcium 2004 Oct;14(10):85-93.PMID:15577137doi
Estrogen replacement therapy, in spite of efficacy in the prevention of osteoporotic fractures, has significant side effects and risks that limit its widespread usage in postmenopausal women. Thus significant medical need exists to find modalities that prevent osteoporosis, but without the side effects of estrogen. Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Tamoxifen, a first generation SERM is approved for the prevention and treatment of breast cancer, and raloxifene, a second generation SERM has been approved for the prevention and treatment of osteoporosis. Lasofoxifene, a new potent, nonsteroidal SERM, binds with high affinity to human estrogen receptors and acts as a tissue selective estrogen antagonist or agonist. In preclinical models of postmenopausal osteoporosis, Lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton. In studies designed to investigate the combination of Lasofoxifene with estrogen, Lasofoxifene blocked the hypertrophic effects of estrogen in the uterus, but did not block the bone protective effects. In immature and aged female rats, Lasofoxifene did not affect the uterine weight and uterine histology. In preclinical studies designed to evaluate the effects of Lasofoxifene on the uterus, a slight increase in wet uterine weight was observed in immature and aged female rats, but this difference was not observed in dry uterine weight suggesting that the increased uterine weight was due to increased water content in the tissue. In preclinical studies designed to evaluate the effects of Lasofoxifene in breast cancer, Lasofoxifene inhibited breast tumor formation in mice injected with human MCF-7 breast cancer cells and in rats bearing mammary carcinomas. Thus, in preclinical models, Lasofoxifene, a next generation SERM, prevents estrogen deficiency-induced bone loss, inhibits breast tumor formation, and reduces serum cholesterol, without causing uterine hypertrophy. These data suggest that Lasofoxifene is a new potential therapy for the prevention of osteoporosis in postmenopausal women.
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer
Breast Cancer Res 2021 May 12;23(1):54.PMID:33980285DOI:10.1186/s13058-021-01431-w.
Background: Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of Lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of Lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. Methods: Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with Lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. Results: As a monotherapy, Lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both Lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of Lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that Lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of Lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. Conclusions: We report for the first time the anti-tumor activity of Lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using Lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.