title: Discovery of a novel, orally active, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist.
abstract: Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).
authors.affiliation: Department of Medicinal Chemistry, Research Pharmacology, and Pharmacokenetics, Dynamics & Metabolism, Pfizer Global Research & Development, 10770 Science Center Drive, San Diego, California 92121, USA. haitao.li@pfizer.com
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Kenna L
authors.initials: KL
authors.lastname: Anderes
authors.forename: Eugenia A
authors.initials: EA
authors.lastname: Kraynov
authors.forename: David R
authors.initials: DR
authors.lastname: Luthin
authors.forename: Quyen-Quyen
authors.initials: QQ
authors.lastname: Do
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Hong
authors.forename: Eileen
authors.initials: E
authors.lastname: Tompkins
authors.forename: Eric T
authors.initials: ET
authors.lastname: Sun
authors.forename: Ranjan
authors.initials: R
authors.lastname: Rajapakse
authors.forename: Ved P
authors.initials: VP
authors.lastname: Pathak
authors.forename: Lance C
authors.initials: LC
authors.lastname: Christie
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Haresh
authors.initials: H
authors.lastname: Vazir
authors.forename: Rosemary
authors.initials: R
authors.lastname: Castillo
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Gregory
authors.forename: Mary
authors.initials: M
authors.lastname: Castro
authors.forename: Karen
authors.initials: K
authors.lastname: Nared-Hood
authors.forename: Genevieve
authors.initials: G
authors.lastname: Paderes
authors.forename: Mark B
authors.initials: MB
authors.lastname: Anderson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009919:Orchiectomy; D010902:Pituitary Gland / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007192:Indenes; D007295:Inositol Phosphates; D009025:Morpholines; C511638:N-(4,6-dimethoxy-2-((3-morpholin-4-ylpropyl)amino)pyrimidin-5-yl)-5-(3,3,6-trimethyl-2,3-dihydro-1H-inden-5-yloxy)-2-furamide; D011743:Pyrimidines; D011966:Receptors, LHRH; D011994:Recombinant Proteins; D013739:Testosterone