In vitro and in vivo activities of reduced-size antagonists of luteinizing hormone-releasing hormone

Haviv, F.; Fitzpatrick, T.D.; Nichols, C.J.; Bush, E.N.; Diaz, G.; Bammert, G.; Nguyen, A.T.; Johnson, E.S.; Knittle, J.; Greer, J.

Journal of Medicinal Chemistry 37(5): 701-705


ISSN/ISBN: 0022-2623
PMID: 7510341
DOI: 10.1021/jm00031a021
Accession: 008835543

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A novel series of octapeptide LHRH antagonists was designed on the basis of the structure of the (2-9) fragment of a LHRH agonist. By adopting a systematic SAR study, we were able to improve first the in vitro activity and then the in vivo LH suppression, raising them up to the range of the decapeptide antagonists NalGlu (51) and A-75998 (50), resulting in A-76154 (49). The octapeptide antagonist A-76154 is the most potent reduced-size LHRH antagonist reported. It suppresses LH in the castrated rat by over 80% for a period of 4 h following sc bolus administration of 30 mu-g/kg.