Potent gonadotropin releasing hormone antagonists with low histamine- releasing activity

Article abstract of DOI:10.1021/jm00099a023

The incorporation of Arg residues into position 6 of gonadotropin releasing hormone antagonists had resulted in compounds with increased in vivo potency but also made these analogues potent mast cell degranulators. We have focused on the substitution of position 8 by hArg(R)₂ (N(G)-N(G)'- dialkylhomoarginine) substitutions, based on the hypotheses that the Arg-Pro sequence is of major importance for this side effect and that shielding of the charge may be an effective way to block degranulation. Analogues in four series were evaluated: (A) [N-Ac-D-Nal(2)¹,D-pCl-Phe²,D-Pal- (3)^3,6,Arg⁵,hArg(R)₂⁸,D-Ala¹⁰]GnRH, (B) [N-Ac-D-Nal(2)¹,D-pCl- Phe²,D-Pal(3)^3,6,hArg(R)₂^5,8,D-Ala¹⁰]-GnRH, (C) [N-Ac-D-Nal(2)¹,D- pCl-Phe²,D-Pal(3)^3,6,hArg(R)₂⁸,D-Ala¹⁰]GnRH, (D) [N-Ac-D-Nal(2)¹,D- pCl-Phe²,D-Pal(3)³,D-hArg(R)₂⁶,hArg(R)₂⁸,D-Ala¹⁰]GnRH. Although substitution by hArg(Et)₂, hArg(Bu), hArg(CH₂)₃, and hArg(CH₂CF₃)₂ was tested, in each series the hArg(Et)₂ residue was superior. Two compounds were considered for clinical evaluation: [N-Ac-D-Nal(2)¹,D-pCl-Phe²,D- Pal(3)^3,6,hArg(Et)₂⁸,D-Ala¹⁰]GnRH and [N-Ac-D-Nal(2)¹,D-pCl-Phe²,D- Pal(3)³,D-hArg(Et)₂⁶,hARg-(Et)₂⁸,D-Ala¹⁰]GnRH (ganirelix acetate). These compounds had high potency for ovulation suppression and low histamine- releasing potency in vitro (ED₅₀ = 0.6, 0.29 μg/rat and EC₅₀ = 196, 13 μg/mL, respectively). Ganirelix is currently in Phase II clinical trials and appears to be the most potent GnRH antagonist tested in humans (based upon ED₅₀ for 24-h suppression of testosterone levels).