Synthesis and biological evaluation of piperazinyl heterocyclic antagonists of the gonadotropin releasing hormone (GnRH) receptor.
Antagonism of the gonadotropin releasing hormone (GnRH) receptor has resulted in positive clinical results in reproductive tissue disorders such as endometriosis and prostate cancer. Following the recent discovery of orally active GnRH antagonists based on a 4-piperazinylbenzimidazole template, we sought to investigate the properties of heterocyclic isosteres of the benzimidazole template. We report here the synthesis and biological activity of eight novel scaffolds, including imidazopyridines, benzothiazoles and benzoxazoles. The 2-(4-tert-butylphenyl)-8-(piperazin-1-yl)imidazo[1,2-a]pyridine ring system was shown to have nanomolar binding potency at the human and rat GnRH receptors as well as functional antagonism in vitro. Additional structure-activity relationships within this series are reported along with a pharmacokinetic comparison to the benzimidazole-based lead molecule.
Department of Chemical, Wyeth Research, Collegeville, PA 19426, USA.
Matthew D
MD
Vera
Joseph T
JT
Lundquist
Murty V
MV
Chengalvala
Joshua E
JE
Cottom
Irene B
IB
Feingold
Lloyd M
LM
Garrick
Daniel M
DM
Green
Diane B
DB
Hauze
Charles W
CW
Mann
John F
JF
Mehlmann
John F
JF
Rogers
Linda
L
Shanno
Jay E
JE
Wrobel
Jeffrey C
JC
Pelletier
D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*
D006571:Heterocyclic Compounds; D010879:Piperazines; D011966:Receptors, LHRH