Patent Evaluation: LHRH Peptides as LHRH Antagonists

Summary

Novelty: Glycosylated or polyhydroxylated leutinizing hormone releasing hormone (LHRH) peptides are disclosed and are proposed to possess LHRH antagonist activity. LHRH antagonists are potentially useful for the suppression of gonadotropin (leutinizing hormone, LH) secretion and hence may be useful for the suppression of female ovulation or male spermatogenesis. Glycosylated/polyhydroxylated calcitonins are also disclosed and are potentially useful for reducing plasma calcium levels and maintaining bone mass.

Biology: The glycosylated LHRH peptides were active in suppressing LHRH-induced LH release from rat pituitary cell culture, and in suppressing ovulation in rats, at doses of between 0.0005–10.0 mg/kg sc. The glycosylated calcitonins are stated to have reduced in vivo plasma calcium levels in rats. However, no specific data are presented.

Chemistry: Glycosylation or polyhydroxylation of the peptides is targetted towards the omega-amino groups of peptide lysine residues, the reaction being an Amadori rearrangement mediated by direct rather than N-glycosidic bonding. This method forms a subsidiary part of the claim and is exemplified in twenty-four cases. A specified example is CH₃CO-DPhe(p-Cl)-DPhe(p-Cl)-DTrp-Ser-Tyr-DLys(formyl)-Leu-Lys(N^η-1-deoxyfructosyl)-Pro-DAla-NH₂.