Figure 5. Compound 8 displayed extended t_1/2 and superior efficacy in rats.

(a) Evaluation of the pharmacokinetic properties of 8 in rats. Equivalent amounts of GnRH-A and 8 were administered at time 0 (single i.v. bolus; 3.3 μmole/kg of each compound) to two groups of male rats (N = 3 for each group); one group was pretreated with vehicle (untreated) while the other group was pretreated with AG10 (AG10-treated group; 17.1 μmole/kg, i.v.). The concentration of test compounds in plasma was determined using validated HPLC method and plotted as a function of time after dosing. Concentrations are expressed as means (±SEM) of three biological replicates. (b) Evaluating the efficacy of 8 in rats. Administration of 8 (single i.v. bolus; 225 ng/kg, 120 picomoles/kg) to gonad-intact male rats (N = 4) stimulated the release of testosterone and maintains higher levels of testosterone in circulation compared to administration of equivalent dose of GnRH-A (single i.v. dose; 150 ng/kg, 120 picomoles/kg) to a second group of rats (N = 4). For control, a third group (N = 3) of rats was administered only vehicle. Testosterone levels in serum were determined using ELISA and concentrations were expressed as means (±SEM) of four biological replicates. *p<0.05, **p<0.01, ***p<0.001, ns – not significant.