Erteberel (LY500307)

2 years -80 in solvent

Oral gavage daily

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.

Dissolved in the solution containing 1% carbxymethyl cellulose and 0.25% Tween 80.

LY500307 shows potent binding affinity for both ERalpha (Ki 2.68 nM) and ERbeta (Ki 0.19 nM), which exhibits 14-fold binding selectivity for the beta isoform, generated using 3H-estradiol and recombinant, full-length, human ERs in a competitive binding assay. LY500307 shows full agonist function in both ERalpha and ERbeta assays (>90% relative efficacy), displays potent inhibition toward ERbeta with EC50 of 0.66 nM exhibiting 32 fold specificity for ERbeta than for ERalpha which has EC50 of 19.4 nM measured using a transcription assay in the cotransfected human prostate cancer PC3/ER (alpha or beta)-ERE cell line. LY500307/ERalpha and LY500307/ERbeta 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. 180C) 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 ERbeta. [1]

Cell-Based Transcriptional Assays, PC3 human prostatic adenocarcinoma cells are transiently cotransfected with plasmid carrying either full length human ERalpha or full length human ERbeta and a reporter plasmid using fugene 6 transfection reagent. Human ERalpha or human ERbeta 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.

LY500307 is a potent, selective estrogen receptor β agonist with EC50 of 0.66 nM, 32-fold selectivity against estrogen receptor α. Phase 2.

LY500307 shows significantly higher binding activity toward ERbeta than ERalpha.