Small molecule antagonists of the gonadotropin-releasing hormone (GnRH) receptor: Structure–activity relationships of small heterocyclic groups appended to the 2-phenyl-4-piperazinyl-benzimidazole template

Abstract A previous report described the serum LH suppression pharmacology of the 2-phenyl-4-piperazinyl-benzimidazole N -ethyluracil GnRH receptor antagonist 1 following oral administration in rats. A series of small heterocycles were appended to the 2-(4- tert -butylphenyl)-4-piperazinyl-benzimidazole template in place of the N -ethyluracil. Two imidazole analogues, 32 and 41 , were shown to possess substantial in vitro potency at the target receptor (hGnRH IC 50  = 7 and 18 nM, respectively) and aqueous solubility (55 and 100 μg/mL at pH 7.4, respectively). Both compounds had high oral bioavailability in rats and 32 was further examined in an orchidectomized rat model for serum LH suppression based on increased volume of distribution over 41 . Serum LH levels trended lower in orchidectomized rats following oral administration of 32 .