Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R).
A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.
Pelletier
Jeffrey C
JC
Department of Chemical Sciences, Musculoskeletal Biology, and Drug Safety and Metabolism, Wyeth Research, Collegeville, Pennsylvania 19426, USA.
Chengalvala
Murty V
MV
Cottom
Joshua E
JE
Feingold
Irene B
IB
Green
Daniel M
DM
Hauze
Diane B
DB
Huselton
Christine A
CA
Jetter
James W
JW
Kopf
Gregory S
GS
Lundquist
Joseph T
JT
Magolda
Ronald L
RL
Mann
Charles W
CW
Mehlmann
John F
JF
Rogers
John F
JF
Shanno
Linda K
LK
Adams
William R
WR
Tio
Cesario O
CO
Wrobel
Jay E
JE
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009919:Orchiectomy; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C540190:6-((4-(2-(4-tert-Butylphenyl)-1H-benzimidazol-4-yl)piperazin-1-yl)methyl)quinoxaline; D001562:Benzimidazoles; D011810:Quinoxalines; D011966:Receptors, LHRH; D007986:Luteinizing Hormone