Synthesis and Bioassay of Antagonists of the Luteinizing Hormone Releasing Hormone Having the Azagly10 Moiety

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Abstract
Seven new analogs of LHRH, having an azaglycinamide moiety in position 10 [Azagly10], and 3 corresponding Gly10-analogs were synthesized for bioassay and comparison of inhibitory potencies. A possible advantage of the Azagly10 moiety to minimize C-terminal degradation, in vivo, was studied. Of the 3 procedures which were studied to achieve Azagly10 peptides, the reaction of cyanate ion with hydrazides was the most favorable. Variations of substitution in position 1 were also studied. The data from the antiovulatory assay showed that an Azagly moiety may not depress activity, and may allow equal or even higher activity than the Gly10 moiety, depending on the analog. [N-Ac-D-Thr1,D-p-Cl-Phe2,D-Trp3,6,Azagly10]-LHRH was more inhibitory than the corresponding Gly10-analog. Based on pairs of analogs, the following relationships appeared: N-Ac-D Thr1 was more effective than N-Ac-p-Cl-Phe1: the L-configuration of Ala as N-Ac-Ala1- was more effective than the D-; N-Ac-Ala1 appeared more effective than the N-Ac-D-Thr1; D-Trp6 appeared more effective than D-Phe6. In an ultimate clinical use of an antagonist of LHRH to block ovulation, the Azagly10 moiety may be advantageous for limitation of enzymatic degradation.