The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists |
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Authors: | Luthin David R Hong Yufeng Pathak Ved P Paderes Genevieve Nared-Hood Karen D Castro Mary A Vazir Haresh Li Haitao Tompkins Eileen Christie Lance May John M Anderson Mark B |
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Affiliation: | Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. david.luthin@pfizer.com |
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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. |
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