GNRH antagonists XIII

摘要

Analogs of the decapeptide GnRH which include two significantly modified amino acids at positions 5 and 6 inhibit the secretion of gonadotropins by the pituitary gland and inhibit the release of steroids by the gonads. Administration of an effective amount of such GnRH antagonists prevents ovulation of female mammalian eggs and/or the release of steroids by the gonads and may be used to treat steroid-dependent tumors. Particularly effective peptides which are soluble in water at physiologic pH and which have a low tendency to gel when administered in vivo have the following formula: Ac- beta -D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Q1)(3-amino-1,2,4 triazole)-D-Aph(Q2)(3-amino 1,2,4-triazole)-Leu-Lys (isopropyl)-Pro-D-Ala-NH2, where Q1 and Q2 are amino acids, such as Gly, beta -Ala, Ala, D-Ala, Ser, Aib, Ahx and Gab. Examples of other GnRH antagonists include Ac- beta -D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Atz)-D-Aph(Ac)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2, Ac- beta -D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph( beta -Ala)(3-amino-1,2,4 triazole)-D-Aph( beta -Ala)(3-amino-1,2,4 triazole)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2, Ac- beta -D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Ac-D-Ser)-D-Aph(Ac-D-Ser)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2, and Ac- beta -D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Ac)-D-Aph(Ac)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2.