Arzoxifene / LY 353381 CAS No. 182133-25-1

Product Description

Arzoxifene (development code LY 353381) is a third-generation selective estrogen receptor modulator (SERM) developed by Eli Lilly and Company that combines the antiestrogenic properties of tamoxifen with the tissue-selective safety advantages of raloxifene, acting as an antagonist in breast and uterine tissues and an agonist in the bone and cardiovascular system. This synthetic aromatic derivative binds to the estrogen receptor as a mixed agonist/antagonist and is rapidly converted to its active metabolite, demethylarzoxifene, which has higher bioavailability in the breast and stronger antiestrogenic effects than raloxifene, but less uterine stimulation than tamoxifen or raloxifene. Arzoxifene has been extensively studied in Phase III clinical trials for nine indications of osteoporosis and breast cancer prevention in postmenopausal women, with results showing significant reductions in the incidence of vertebral fractures and breast cancer, but ultimately failed to meet secondary endpoints; Eli Lilly discontinued development of the drug in 2009, making it an experimental compound that never made it to the market.

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Product Use & Characteristics

Chemical Identity & Structure

• IUPAC Name: 2-(4-methoxyphenyl)-3-[4-(2-piperidin-1-ylethoxy)phenoxy]-1-benzothiophen-6-ol

• Molecular Formula: C₂₈H₂₉NO₄S

• Molecular Weight: 475.6 g/mol

• Class: 3rd-generation benzothiophene-derived SERM

Mechanism of Action

• ER-α/β antagonist in breast (anti-proliferative) and uterus (no stimulation)

• ER agonist in bone (increases BMD) and cardiovascular system (lowers LDL-C)

• Prodrug: Rapidly demethylated to desmethylarzoxifene (DMA), a more potent metabolite

Pharmacology & Potency

• Anti-breast cancer potency: 8× stronger than raloxifene

• IC₅₀ (MCF-7 cells): 0.4 nM (vs tamoxifen 480 nM)

• Uterine anti-estrogenic ED₅₀: 0.01 mg/kg (rat)

Uses (Investigated)

• Osteoporosis (post-menopausal women)

• Breast cancer prevention (ER-positive invasive breast cancer)

Clinical Trials & Efficacy

• FOUNDATION (2 yrs, n=331): ↑ lumbar spine & total hip BMD vs placebo

• GENERATIONS (5 yrs, n=9,354):

  • ↓ Vertebral fractures (HR 0.59)

  • ↓ Invasive breast cancer (HR 0.42, 70% ER-positive reduction)

  • No non-vertebral fracture benefit

Safety & Adverse Effects

• Endometrium: Neutral (unlike tamoxifen)

• Thromboembolism: ↑ Risk (OR 2.55)

• Hot flashes reported

Development Status

• Discontinued (2009) – Phase III halted by Eli Lilly due to:

  • Lack of non-vertebral fracture efficacy

  • Side-effect profile (thrombosis, hot flashes)

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