title: 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).
abstract: 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.
authors.affiliation: Department of Chemical Sciences, Musculoskeletal Biology, and Drug Safety and Metabolism, Wyeth Research, Collegeville, Pennsylvania 19426, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Pelletier
authors.forename: Murty V
authors.initials: MV
authors.lastname: Chengalvala
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Cottom
authors.forename: Irene B
authors.initials: IB
authors.lastname: Feingold
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Green
authors.forename: Diane B
authors.initials: DB
authors.lastname: Hauze
authors.forename: Christine A
authors.initials: CA
authors.lastname: Huselton
authors.forename: James W
authors.initials: JW
authors.lastname: Jetter
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Kopf
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Lundquist
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Charles W
authors.initials: CW
authors.lastname: Mann
authors.forename: John F
authors.initials: JF
authors.lastname: Mehlmann
authors.forename: John F
authors.initials: JF
authors.lastname: Rogers
authors.forename: Linda K
authors.initials: LK
authors.lastname: Shanno
authors.forename: William R
authors.initials: WR
authors.lastname: Adams
authors.forename: Cesario O
authors.initials: CO
authors.lastname: Tio
authors.forename: Jay E
authors.initials: JE
authors.lastname: Wrobel
mesh_terms: 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
chemical_list: 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