A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones as potent, stable GnRH receptor antagonists.
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.
Tucci
Fabio C
FC
Neurocrine Biosciences, Inc., San Diego, CA 92121, USA. ftucci@neurocrine.com
Zhu
Yun-Fei
YF
Guo
Zhiqiang
Z
Gross
Timothy D
TD
Connors
Patrick J
PJ
Struthers
R Scott
RS
Reinhart
Greg J
GJ
Wang
Xiaochuan
X
Saunders
John
J
Chen
Chen
C
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
D011744:Pyrimidinones; D011758:Pyrroles; D011966:Receptors, LHRH; D011994:Recombinant Proteins; D002118:Calcium