Advancements in GnRH Antagonism: Exploring the Role of p-Ureido-Phenylalanine in Prolonging Action Duration

A collection of gonadotropin-releasing hormone (GnRH) antagonists was synthesized and evaluated for their effectiveness in inhibiting luteinizing hormone release in castrated male rats. These compounds were designed with urea/carbamoyl functionalities at positions P and Q to enhance hydrogen bonding, stabilize the structure, and improve peptide/receptor interactions. The modifications led to increased hydrophilicity and reduced gel formation in aqueous solutions compared to azaline B.

Among the synthesized analogues, FE200486 (acetate salt) and eight others demonstrated a significantly prolonged duration of action compared to acyline when administered subcutaneously. Notably, FE200486 maintained plasma concentrations above a certain threshold for an extended period, correlating with the suppression of plasma LH levels.

The study found no direct relationship between hydrophilicity, as measured by retention times on a C18 reverse phase column, or affinity in an in vitro human GnRH report gene assay (pA2), and the duration of action. FE200486 was chosen for further preclinical studies, where it showed a longer-lasting inhibition of plasma testosterone compared to other GnRH antagonists like ganirelix, abarelix, and azaline B.

The unique physicochemical properties of FE200486, such as its solubility in aqueous environments and low propensity to form gels, are believed to contribute to its extended duration of action. Furthermore, FE200486 exhibited lower potency in releasing histamine from isolated rat mast cells compared to other preclinical GnRH antagonists.