2-phenyl-4-piperazinylbenzimidazoles: orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor.
Antagonism of the gonadotropin releasing hormone (GnRH) receptor has shown positive clinical results in numerous reproductive tissue disorders such as endometriosis, prostate cancer and others. Traditional therapy has been limited to peptide agonists and antagonists. Recently, small molecule GnRH antagonists have emerged as potentially new treatments. This article describes the discovery of 2-phenyl-4-piperazinylbenzimidazoles as small molecule GnRH antagonists with nanomolar potency in in vitro binding and functional assays, excellent bioavailability (rat %F>70) and demonstrated oral activity in a rat model having shown significant serum leuteinizing hormone (LH) suppression.
Department of Chemical & Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. Pelletj@wyeth.com
Jeffrey C
JC
Pelletier
Murty
M
Chengalvala
Josh
J
Cottom
Irene
I
Feingold
Lloyd
L
Garrick
Daniel
D
Green
Diane
D
Hauze
Christine
C
Huselton
James
J
Jetter
Wenling
W
Kao
Gregory S
GS
Kopf
Joseph T
JT
Lundquist
Charles
C
Mann
John
J
Mehlmann
John
J
Rogers
Linda
L
Shanno
Jay
J
Wrobel
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry; D006016:Glycolates / Q000737:chemistry; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008745:Methylation; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D003432:Cross-Linking Reagents; D006016:Glycolates; D010879:Piperazines; D011966:Receptors, LHRH; D000077489:Piperazine; C053956:glycolamide; D007986:Luteinizing Hormone