Physicochemical Properties
| Molecular Formula | C28H31NO2 |
| Molecular Weight | 413.56 |
| Exact Mass | 413.235 |
| Elemental Analysis | C, 68.19; H, 6.62; N, 2.49; O, 22.71 |
| CAS # | 190791-29-8 |
| Related CAS # | Lasofoxifene;180916-16-9 |
| PubChem CID | 3081919 |
| Appearance | White to off-white solid powder |
| Boiling Point | 572.4ºC at 760 mmHg |
| Melting Point | 185 °C(dec.) |
| Flash Point | 300ºC |
| Vapour Pressure | 1.05E-13mmHg at 25°C |
| LogP | 6.468 |
| Hydrogen Bond Donor Count | 5 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 9 |
| Heavy Atom Count | 41 |
| Complexity | 667 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | C1CCN(C1)CCOC2=CC=C(C=C2)[C@H]3[C@H](CCC4=C3C=CC(=C4)O)C5=CC=CC=C5.[C@H]([C@@H](C(=O)O)O)(C(=O)O)O |
| InChi Key | INEHJXCWEVNEDZ-LUDNRVPPSA-N |
| InChi Code | InChI=1S/C28H31NO2.C4H6O6/c30-24-11-15-27-23(20-24)10-14-26(21-6-2-1-3-7-21)28(27)22-8-12-25(13-9-22)31-19-18-29-16-4-5-17-29;5-1(3(7)8)2(6)4(9)10/h1-3,6-9,11-13,15,20,26,28,30H,4-5,10,14,16-19H2;1-2,5-6H,(H,7,8)(H,9,10)/t26-,28+;1-,2-/m10/s1 |
| Chemical Name | (2S,3S)-2,3-dihydroxybutanedioic acid;(5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol |
| Synonyms | CP-336156; Fablyn; 190791-29-8; LASOFOXIFENE HCL; Fablyn; Lasofoxifene (Tartrate); CP-336156; Lasofoxifene tartrate [USAN]; 85X09V2GSO; Lasofoxifene tartrate |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | ER; selective estrogen receptor modulator (SERM) |
| ln Vitro | Regardless of the expression levels of activating ERα mutations, lasofoxifene tartrate (1 nM-1 μM; 48 h) exhibits antagonist activity in ER+ breast cancer cells in comparison to wild-type (WT) ERα [2]. |
| ln Vivo | To lessen the severity of arthritis, lasoxifene tartrate (4 mg/mouse; SC; 5 days/week; for 43 days) decreases serum levels of IL-6, an inflammatory cytokine, and cartilage oligomeric matrix protein (COMP), a marker of cartilage degradation [1]. By boosting trabecular bone mineral density (BMD) and cortical thickness in mice, lasoxifene tartrate (4 mg/mouse; subcutaneous injection; 5 days/week; for 43 d) prevents systemic bone loss in CIA [1]. In mice, the subcutaneous injection of lasoxifene tartrate (5 and 10 mg/kg) five days a week for seventy days slows the growth of primary tumors and decreases liver and lung metastases [3]. |
| Cell Assay |
Lasofoxifene, a SERM originally developed for the treatment/prevention of osteoporosis, was the only compound found to be as potent an antagonist when evaluated in cells expressing ERY537S or ERD538G when compared to ERWT (Fig. 2I). This latter observation is in agreement with the findings of a recent study from our group showing that lasofoxifene was as effective an inhibitor of ERmuts as ERWT in cellular models of gynecological cancers. These findings have important clinical implications that could inform the optimal selection of ER antagonists for the treatment of patients with ERmuts in advanced disease[2]. Considering the pharmacology noted in SKBR3 cells, we selected fulvestrant (potency shift observed with both mutants), AZD9496 (loss of efficacy as an inhibitor of ERY537S) and lasofoxifene (potency and efficacy unaffected by mutation status) for analysis in these model systems. The transcriptional activity and pharmacology of receptor combinations were assessed using a transfected ERE-luciferase reporter gene[2]. |
| Animal Protocol |
Animal/Disease Models: OVX (ovariectomized) DBA/1 mouse postmenopausal RA model (female DBA/1 mice, 8-10 weeks old, CIA treated) [1] Doses: 4 mg/mouse/day Route of Administration: subcutaneous injection; 5 days per week from first signs of arthritis (Day 18); 43 days Experimental Results: Reduction in arthritis severity, including reduction in synovial inflammation and joint destruction. At 42 days post-immunization, the average incidence of arthritis was 47% compared with 81% in the vehicle group. Animal/Disease Models: NSG Mouse xenograft tumor model (MIND, mammary intraductal): WT, Y537S and D538G ERα renders tumors [3] Doses: 1, 5 or 10 mg/kg Route of Administration: SC; 5 days per week ; 70-day Experimental Results: Excellent inhibitory effect at 10 mg/kg, resulting in potential tumor shrinkage of Y537S and D538G tumors. At doses of 5 mg/kg and 10 mg/kg, tumor weight was diminished to 60% and 50% for Y537S and D538G, respectively. Female DBA/1 mice were ovariectomised and subjected to CIA as a model of post-menopausal RA. Mice received treatment with LAS, BZA, 17β-estradiol (E2) as reference or vehicle. Arthritis development was assessed and BMD was determined by peripheral quantitative CT of the femurs. Serologic markers of inflammation and cartilage destruction were analysed. Immune cells in lymph nodes were studied by flow cytometry.[1] 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.[3] |
| References |
[1]. Selective oestrogen receptor modulators lasofoxifene and bazedoxifene inhibit joint inflammation and osteoporosis in ovariectomised mice with collagen-induced arthritis. Rheumatology (Oxford). 2016 Mar;55(3):553-63. [2]. The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor. Mol Cancer Ther. 2020 Jul. 19(7):1395-1405. [3]. Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer. Breast Cancer Res. 2021 May 12. 23(1):54. |
| Additional Infomation |
Lasofoxifene Tartrate is the tartrate salt form of lasofoxifene, a non-steroidal, naphthalene-derived, third-generation selective estrogen receptor modulator (SERM) with potential antineoplastic and anti-osteoporotic activities. Upon oral administration, lasofoxifene selectively binds to both estrogen receptor alpha (ERalpha; ESR1) and estrogen receptor beta (ERbeta; ESR2) with high affinity and mimics the effects of endogenous estradiol with varying agonist and antagonist effects in ER-expressing tissues. Blockade of ERalpha by lasofoxifene may potentially inhibit estrogen-dependent cancer cell proliferation in ER-expressing cancers. Lasofoxifene may also bind to the certain mutant forms of ERalpha, including the Y537S ESR1 mutant, making it potentially useful in the treatment of tumors that have acquired resistance to other ER-targeting agents. Drug Indication Fablyn is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. A significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated (see section 5. 1). When determining the choice of Fablyn or other therapies, including oestrogens, for a postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5. 1). Treatment of osteoporosis in postmenopausal women at increased risk of fracture |
Solubility Data
| Solubility (In Vitro) | DMSO : ~83.33 mg/mL (~147.84 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (3.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4180 mL | 12.0901 mL | 24.1803 mL | |
| 5 mM | 0.4836 mL | 2.4180 mL | 4.8361 mL | |
| 10 mM | 0.2418 mL | 1.2090 mL | 2.4180 mL |