(2R,6S,7R)-7-(4-hydroxyphenyl)-8-oxatricyclo[7.4.0.0^{2,6}]trideca-1(13),9,11-trien-12-ol

• ChemBase编号: 5563
• 分子式: C18H18O3
• 平均质量: 282.33372
• 单一同位素质量: 282.12559444
• SMILES: [C@H]12c3cc(ccc3O[C@H]([C@H]1CCC2)c1ccc(cc1)O)O
• Canonical SMILES: Oc1ccc(cc1)[C@@H]1Oc2ccc(cc2[C@H]2[C@@H]1CCC2)O
• InChI: InChI=1S/C18H18O3/c19-12-6-4-11(5-7-12)18-15-3-1-2-14(15)16-10-13(20)8-9-17(16)21-18/h4-10,14-15,18-20H,1-3H2/t14-,15+,18+/m1/s1
• InChIKey: XIESSJVMWNJCGZ-VKJFTORMSA-N

名称和登记号

名称

• IUPAC标准名: (2R,6S,7R)-7-(4-hydroxyphenyl)-8-oxatricyclo[7.4.0.0^{2,6}]trideca-1(13),9,11-trien-12-ol; (2R,6S,7R)-7-(4-hydroxyphenyl)-8-oxatricyclo[7.4.0.0^{2,6}]trideca-1(9),10,12-trien-12-ol
• IUPAC传统名: (2R,6S,7R)-7-(4-hydroxyphenyl)-8-oxatricyclo[7.4.0.0^{2,6}]trideca-1(13),9,11-trien-12-ol; (2R,6S,7R)-7-(4-hydroxyphenyl)-8-oxatricyclo[7.4.0.0^{2,6}]trideca-1(9),10,12-trien-12-ol
• 别名: (3AS,4R,9BR)-4-(4-HYDROXYPHENYL)-1,2,3,3A,4,9B-HEXAHYDROCYCLOPENTA[C]CHROMEN-8-OL; LY500307

登记号

• CAS号: 533884-09-2
• PubChem SID: 160968991; 99444404
• PubChem CID: 10286159

理论计算性质

JChem

• Acid pKa: 9.352871
• 质子受体: 3
• 质子供体: 2
• LogD (pH = 5.5): 4.1099153
• LogD (pH = 7.4): 4.10518
• Log P: 4.109976
• 摩尔折射率: 80.4954 cm^3
• 极化性: 31.31295 Å^3
• 极化表面积: 49.69 Å^2
• 可自由旋转的化学键: 1
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 3.85
• LOG S: -4.24
• 溶解度: 1.62e-02 g/l

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: ERβ

产品相关信息

• 成盐信息: Free Base

详细说明

DrugBank - DB07933

Drug information: experimental

Selleck Chemicals - S1598

Research Area

• Description: Endocrinology

Biological Activity

• Description: LY500307 (SERBA-1) is a potent, selective estrogen receptor β agonist with EC50 of 0.66 nM.
• Targets: Estrogen receptor β
• IC50: 0.66 nM (EC50) ^[1]
• In Vitro: LY500307 shows potent binding affinity for both ERα (K_i 2.68 nM) and ERβ (K_i 0.19 nM), which exhibits 14-fold binding selectivity for the β isoform, generated using 3H-estradiol and recombinant, full-length, human ERs in a competitive binding assay. LY500307 shows full agonist function in both ERα and ERβ assays (>90% relative efficacy), displays potent inhibition toward ERβ with EC50 of 0.66 nM exhibiting 32 fold specificity for ERβ than for ERα which has EC50 of 19.4 nM measured using a transcription assay in the cotransfected human prostate cancer PC3/ER (α or β)-ERE cell line. LY500307/ERα and LY500307/ERβ X-ray cocrystal structures show significant differences in the manner in which LY500307 binds within the binding pockets. LY500307 displays a different orientation corresponding to a (ca. 180°) rotation on its bisphenol axis, and the A ring phenol of LY500307, while bound to histidine in both structures, locates to different sides of the imidazole functionality for this interaction explaining the observed selectivity of LY500307 for ERβ. ^[1]
• In Vivo: Oral administration of LY500307 (0.01-0.05 mg/kg) in CD-1 mice produces the reduction on prostate weights in a dose-response manner, has no effect on testes and SV weights in this dose range and no effect on T and DHT levels at up to 10× the minimum efficacy dose (0.1 mg/kg), while the nonselective ER agonist diethylstilbestrol (DES) shows significant regression of prostate, testes, and SV and also lowering T and DHT. ^[1]
• Clinical Trials: The phase II study to evaluate daily oral doses of LY500307 for 24 weeks in men with lower urinary tract symptoms (LUTS) and prostatic enlargement secondary to benign prostatic hyperplasia (BPH) has been terminated due to insufficient efficacy.
• Features: LY500307 shows significantly higher binding activity toward ERβ than ERα.

Protocol

• Protocol: Kinase Assay ^[1]
• Cell-Based Transcriptional Assays: PC3 human prostatic adenocarcinoma cells are transiently cotransfected with plasmid carrying either full length human ERα or full length human ERβ and a reporter plasmid using fugene 6 transfection reagent. Human ERα or human ERβ are constitutively expressed using plasmids containing the cytomegalovirus (CMV) promoter. Reporter plasmids for the ER CTF assays contain 3X human ERE plus the thymidine kinase (TK) promoter upstream of the luciferase reporter cDNA. Efficacy is determined relative to the reference molecule diethylstilbestrol. EC50 values are determined by computer fit to a concentration-response curve.
• Protocol: Animal Study ^[1]
• Animal Models: CD-1 mice
• Formulation: Dissolved in the solution containing 1% carbxymethyl cellulose and 0.25% Tween 80.
• Doses: 0.01-0.05 mg/kg
• Administration: Oral gavage daily

References

• References: [1] Norman BH, et al. J Med Chem, 2006, 49(21), 6155-6157.

参考文献

• Norman BH, et al. J Med Chem, 2006, 49(21), 6155-6157.