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.
Pelletier
Jeffrey C
JC
Department of Chemical & Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. Pelletj@wyeth.com
Chengalvala
Murty
M
Cottom
Josh
J
Feingold
Irene
I
Garrick
Lloyd
L
Green
Daniel
D
Hauze
Diane
D
Huselton
Christine
C
Jetter
James
J
Kao
Wenling
W
Kopf
Gregory S
GS
Lundquist
Joseph T
JT
Mann
Charles
C
Mehlmann
John
J
Rogers
John
J
Shanno
Linda
L
Wrobel
Jay
J
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