title: The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. david.luthin@pfizer.com
authors.forename: David R
authors.initials: DR
authors.lastname: Luthin
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Hong
authors.forename: Ved P
authors.initials: VP
authors.lastname: Pathak
authors.forename: Genevieve
authors.initials: G
authors.lastname: Paderes
authors.forename: Karen D
authors.initials: KD
authors.lastname: Nared-Hood
authors.forename: Mary A
authors.initials: MA
authors.lastname: Castro
authors.forename: Haresh
authors.initials: H
authors.lastname: Vazir
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Eileen
authors.initials: E
authors.lastname: Tompkins
authors.forename: Lance
authors.initials: L
authors.lastname: Christie
authors.forename: John M
authors.initials: JM
authors.lastname: May
authors.forename: Mark B
authors.initials: MB
authors.lastname: Anderson
mesh_terms: 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
chemical_list: D006727:Hormone Antagonists; D011966:Receptors, LHRH; D011994:Recombinant Proteins; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D019791:Guanidine