In vitro and in vivo activities of reduced-size antagonists of luteinizing hormone-releasing hormone.
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 micrograms/kg.
Haviv
F
F
TAP Pharmaceuticals, Inc., Abbott Park, Illinois.
Fitzpatrick
T D
TD
Nichols
C J
CJ
Bush
E N
EN
Diaz
G
G
Bammert
G
G
Nguyen
A T
AT
Johnson
E S
ES
Knittle
J
J
Greer
J
J
D000595:Amino Acid Sequence; D000818:Animals; D002369:Castration; D015195:Drug Design; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007986:Luteinizing Hormone / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D010446:Peptide Fragments; C086218:A 76154; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone