GnRH pGlu1-His2-Trp3-Ser4-Tyr5-Glu6-Leu7-Arg8-Pro9-Gly10-NH2

Triptorelin pGlu1-His2-Trp3-Ser4-Tyr5-D-Tryp6-Leu7-Arg8-Pro9-Gly10-NH2

Leuprolide pGlu1-His2-Trp3-Ser4-Tyr5-D-Leu6-Leu7-Arg8-Pro9-NHC2H5

Buserelin pGlu1-His2-Trp3-Ser4-Tyr5-D-Ser(tBu)6-Leu7-Arg8-Pro9-NHC2H5

Goserelin pGlu1-His2-Trp3-Ser4-Tyr5- Ser(tBu)6-Leu7-Arg8-Pro9-AzGly10-NH2

Nafarelin pPyr1-His2-Trp3-Ser4-Tyr5-D-2-Nal6-Leu7-Arg8-Pro9-Gly10-NH2

Figure 42 Peptide GnRH agonists.

GnRH pGlu1 -His2-Trp3-Ser4-Tyr5-Glu6-Leu7-Arg8-Pro9-Gly10-NH2

NaI-Glu-GnRH Ac-D-Nal1-D-Cpa2-D-Pal3-Ser4-Arg5-D-Glu6(AA)-Leu7-Arg8-Pro9-D-Ala10-NH2

Antide Ac-D-Nal1-D-Cpa2-D-Pal3-Ser4-NicLys5-D-NicLys6-Leu7-ILys8-Pro9-D-Ala10-NH2

Cetrorelix Ac-D-Nal1-D-Cpa2-D-Pal3-Ser4-Tyr5-D-Cit6-Leu7-Arg8-Pro9-D-Ala10-NH2

Ganirelix Ac-D-Nal1-D-Cpa2-D-Pal3-Ser4-Tyr5-D-hArg(Et2)6-Leu7-hArg(Et2)8-Pro9-D-Ala10-NH2

Figure 43 Peptide GnRH antagonists.

peptides have been widely used in a clinical setting in which modulation of the production of sex steroid hormones is beneficial to prevent the development or progression of benign conditions (e.g., endometriosis, uterine fibroids) or malignant tumors (e.g., breast, ovarian, endometrial, and prostate carcinoma). GnRH agonists have increased potency for the short-term release of gonadotropins. However, they show paradoxical action in that chronic treatment results in inhibition of GnRH production as a result of desensitization of the gonadotropins and downregulation of its receptor. In contrast, peptidic GnRH antagonists produce a rapid and dose-dependent suppression of gonadotropin release by competitive blockade of the GnRH receptors without any initial stimulatory effect, as seen with agonists. Zoladex is the only GnRH agonist approved by the US Food and Drug Administration for the treatment of metastatic breast cancer in pre- and postmenopausal women. It is administered on a monthly basis as an implant. Response rates range from 30% to 60% in premenopausal women. Major side effects include hot flushes and osteoporosis.

Small-molecule GnRH antagonists have been reported (Figure 44). The first high-affinity nonpeptidic antagonist of the human GnRH receptor T-98475 was reported in 1998.144 Since this initial disclosure, several small molecules from different chemical classes have appeared in the literature. Arylquinolones are potent antagonists of the human (IC50 = 0.44nmolL_ 1) and rat (IC50 = 4nmol L "1) GnRH receptor. Tryptamine GnRH antagonists have demonstrated oral bioavailability in rats and dogs.146 Recently, TAK-013 has been reported to be clinically efficacious in humans in suppressing luteinizing hormone when given orally. A series of pyrazolopyrimidones,148 imidazolopyrimidones,149 and uracils150 have also been reported.

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