Gonadotropin-releasing hormone (
GnRH) receptor agonists have wide clinical applications including the treatment of
prostate cancer and endocrine disorders. However, such agonists are characterized by poor pharmacokinetic properties, often requiring repeated administration or special formulations. Therefore, the development of novel
peptide analogs with enhanced in vivo stability could potentially provide therapeutic alternatives. The pharmacological evaluation of a bioactive
peptide [Des-Gly¹⁰,Tyr⁵(OMe),D-Leu⁶,Aze-NHEt⁹]
GnRH, analog 1, is presented herein and compared with
leuprolide.
Peptide stability was evaluated using mouse kidney membrane preparations, followed by a liquid chromatography-tandem mass spectrometry-based approach that afforded identification and quantification of its major metabolites. The analog was significantly more stable in vitro in comparison with
leuprolide. In vitro and in vivo stability results correlated well, encouraging us to develop a clinically relevant pharmacokinetic mouse model, which facilitated efficacy measurements using
testosterone as a
biomarker. Analog 1, an agonist of the
GnRH receptor with a binding affinity in the nanomolar range, caused
testosterone release in mice that was acutely dose-dependent, an effect blocked by the
GnRH receptor antagonist
cetrorelix. Repeated dosing studies in mice demonstrated that analog 1 was well tolerated and had potency similar to that of
leuprolide, based on plasma and testis
testosterone reduction and histopathological findings. Analog 1 also shared with
leuprolide similar significant antiproliferative activity on
androgen-dependent
prostate cancer (LNCaP) cells. On the basis of pharmacokinetic advantages, we expect that analog 1 or analogs based on this new design will be therapeutically advantageous for the treatment of
cancer and endocrine disorders.