The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists.
A novel series of non-peptide derivatives 1, 14, and 15 that bind with high affinity to the human GnRH receptors is discussed. The discovery was made from screening our in-house libraries that contained the active structure 2 along with a trace amount of a second active structure 1 that was derived from an acid-induced rearrangement. From this structure type 1, a series of guanidine and non-guanidine containing analogues were prepared and tested as GnRH receptor antagonists. Compounds derived from this series bind to both human and rat GnRH receptors and antagonize GnRH-mediated increases in inositol phosphate production in cells containing recombinant human receptors. These compounds or their analogues may be useful as therapeutic agents for the treatment of hormone-dependent pathologies including prostate, breast and ovarian cancers.
Luthin
David R
DR
Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. david.luthin@pfizer.com
Hong
Yufeng
Y
Pathak
Ved P
VP
Paderes
Genevieve
G
Nared-Hood
Karen D
KD
Castro
Mary A
MA
Vazir
Haresh
H
Li
Haitao
H
Tompkins
Eileen
E
Christie
Lance
L
May
John M
JM
Anderson
Mark B
MB
D000818:Animals; D015195:Drug Design; D019791:Guanidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis; D011485:Protein Binding; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D006727:Hormone Antagonists; D011966:Receptors, LHRH; D011994:Recombinant Proteins; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D019791:Guanidine