LU 302 872 and Its Racemate (LU 224 332) Show Balanced Endothelin-A/B Receptor Affinity, High Oral Activity, and Inhibit Human Prostate Tissue Contractions

LU 302 872 (racemate LU 224 332) is a new glycerinic acid derivative related to the selective ETA receptor antagonist LU 135 252. LU 302 872 exhibits high and balanced affinity to ETA and ETB receptors (Ki 2.2 and 5.8 nmol/L), whereas LU 135 252 is ETA-selective (Ki 1.4 and 184 nmol/L). Two hours after oral treatment of rats with 10 mg/kg of LU 302 872 or of LU 135 252, the big ET-1-induced (20 μg/kg i.v.) blood pressure increase is inhibited by 59 ± 8% or 52 ± 2% (n = 6-8; p< 0.05 vs. control), whereas bosentan is without effect (−6 ± 7%;n = 6). In guinea pigs, 10 mg/kg p.o. of LU 302 872 inhibited the big ET-1 (20 μg/kg i.v.)-induced bronchospasm (reduction in respiratory volume) by 78 ± 7% (n = 6; p < 0.05), whereas the ETA antagonist LU 135 252 was ineffective (0.2 ± 37%; n = 6). Hence, a high oral effectiveness of the new ETA/B antagonist could be demonstrated in two species for both an ETA- or an ETB-mediated response. In human prostate tissue (excised during cystectomy in bladder cancer patients), ET-1 and in most cases, the ETB agonist sarafotoxin 6c (S6c) caused contractions of similar magnitude but more sustained than that of norepinephrine (10 mol/L). A high concentration (10 mol/L) of the ETA antagonist LU 135 252 only moderately attenuated ET contractions. The ETA/B antagonist LU 302 872 or its racemate, LU 224 332, dose-dependently inhibited ET-1-induced contractions. S6C dose-response curves, too, were shifted to the right or suppressed by the combined ETA/B antagonist (10 mol/L LU 224 332). LU 302 872 may be a suitable candidate for testing in benign prostate hyperplasia (BPH).