title: A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones as potent, stable GnRH receptor antagonists.
abstract: A new class of small molecule GnRH antagonists, the 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones, was designed and a novel synthesis for these compounds was developed. The synthesis utilizes a base-catalyzed intramolecular cyclization of fluoromethyl pyrimidone 5 to generate the bicyclic core. Amongst the compounds synthesized, we discovered some highly potent GnRH receptor antagonists (e.g., 12, K(i)=9 nM), which showed enhanced stability towards acidic physiological conditions compared to the des-fluoro analogues.
authors.affiliation: Neurocrine Biosciences, Inc., San Diego, CA 92121, USA. ftucci@neurocrine.com
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Gross
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Connors
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Reinhart
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003500:Cyclization; D004355:Drug Stability; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D011744:Pyrimidinones; D011758:Pyrroles; D011966:Receptors, LHRH; D011994:Recombinant Proteins; D002118:Calcium