Gnrh antagonists

Details Gnrh antagonists Gnrh antagonists

C - Chemistry, Metallurgy

07

K

C07K 7/23 (2006.01) A61K 38/09 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2185710

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-(4C1)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-(4C1)D-Phe-D- 3PAL-Ser-Aph(Atz)-D-Aph(Ac)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2, Ac-.beta.-D-2NAL- (4C1)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-(4C1)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-(4C1)D-Phe-D-3PAL-Ser-Aph(Ac)-D-Aph(Ac)- Leu-Lys(isopropyl)-Pro-D-Ala-NH2.

Des analogues du décapeptide anti-gonadolibérine (GnRH) qui comprennent deux acides aminés fortement modifiés en positions 5 et 6 bloquent la sécrétion de gonadotropines par l'hypophyse et bloquent la libération de stéroïdes par les gonades. L'administration d'une dose efficace de ces antagonistes de la GnRH empêche l'ovulation des oeufs chez les mammifères femelles et/ou la libération de stéroïdes par les gonades, et peut être utilisée pour traiter des tumeurs stéroïdo-dépendantes. Les peptides particulièrement efficaces, hydrosolubles à un pH physiologique, et qui ont une tendance à se gélifier lorsqu'ils sont administrés in vivo, ont la formule suivante: Ac-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Q¿1?)(3-amino-1,2,4-triazole)-D-Aph(Q¿2?)(3-amino-1,2,4-triazole)-Leu-Lys(isopropyl)-Pro-D-Ala-NH¿2?. Dans cette formule Q¿1? et Q¿2? sont des acides aminés tels que Gly, .beta.-Ala, Ala, D-Ala, Ser, Aib, Ahx et Gab. On notera également d'autres exemples d'antagonistes de la GnRH dont Ac-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Atz)-D-Aph(Ac)-Leu-Lys(isopropyl)-Pro-D-Ala-NH¿2?, le 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-NH¿2?, le 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-NH¿2?, et le Ac-.beta.-D-2NAL-(4Cl)D-Phe-D-3PAL-Ser-Aph(Ac)-D-Aph(Ac)-Leu-Lys(isopropyl)-Pro-D-Ala-NH¿2?.

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