CHRH antagonists with low histamine release

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Karl A. Folkers
Minoru Kubota
Cyril Y. Bowers
Pui-Fun L. Tang
Anders Ljungqvist
Dong-Mei Feng

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United States Patent and Trademark Office


Antide is the decapeptide, N--Ac--D--2--Nal,D--pClPhe, D--3--Pal, Ser,NicLys, D--NicLys, Leu, ILys, Pro, D--Ala,NH.sub.2 which is an antagonist of luteinizing hormone releasing hormone (LHRH). This decapeptide, like others of the present invention, has high antiovulatory activity (AOA) and releases negligible histamine. Antide is scheduled for scale-up, safety testing and evaluation in the experimental primate and in clinical medicine. Numerous other peptides having structures related to Antide were prepared and tested. These peptides had variations primarily in positions 5, 6, 7, and 8. Of these, N--Ac--D--2--Nal, D--pClPhe,D--3--Pal,Ser,PicLys,cis--DpzACAla, Leu,ILys,pro,D--Ala--NH.sub.2 was one of the most potent and had higher antiovulatory activity than Antide, i.e. 73%/0.25 ug and 100%/0.5 ug vs. 36%/0.5 ug and 100%/1.0 ug. Antide showed significant, (p<0.001) duration of action, when injected at a dose of 10 ug, 44 hours before 50 ng of the agonist, [D--3--Qal.sup.6 ]--LHRH. Antide showed oral AOA at 600 ug (73%) and at 1200 ug (100%) with negligible difference being found between water and corn oil oral formulations.



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