Potent, long-acting luteinizing hormone-releasing hormone antagonists containing new synthetic amino acids: N,N'-dialkyl-D-homoarginines.

A new series of unnatural amino acids has been prepared and incorporated into antagonistic analogues of luteinizing hormone-releasing hormone (LH-RH), on the basis of the hypothesis that stabilization of a proposed phospholipid membrane interaction might yield analogues with high potency and a prolonged duration of action. Thus a series of NG,NG'-dialkyl-D-homoarginine analogues [H-D-hArg(R2)-OH; R = Me, Et, Pr, i-Pr, Bu, hexyl, cyclohexyl, (Et, Me2NPr)] was conveniently prepared by semisynthesis from D-Lys using the appropriate dialkylcarbodiimide. A number of the analogues that were prepared by using these new amino acid analogues exhibited very high potency and a prolonged duration of action. One of the most potent members of the series, [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 ]LH-RH (detirelix), had an ED50 of 0.7 microgram in the rat antiovulatory assay when administered at noon on proestrus and only 2.5 micrograms when administered 24 h earlier, at noon on diestrus II. This antagonist is undergoing detailed biological and clinical evaluation.