title: Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity.
abstract: Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, NJ 07065-0900, Rahway, USA
authors.forename: W T
authors.initials: WT
authors.lastname: Ashton
authors.forename: R M
authors.initials: RM
authors.lastname: Sisco
authors.forename: G R
authors.initials: GR
authors.lastname: Kieczykowski
authors.forename: Y T
authors.initials: YT
authors.lastname: Yang
authors.forename: J B
authors.initials: JB
authors.lastname: Yudkovitz
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.forename: G R
authors.initials: GR
authors.lastname: Mount
authors.forename: R N
authors.initials: RN
authors.lastname: Ren
authors.forename: T J
authors.initials: TJ
authors.lastname: Wu
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.forename: K A
authors.initials: KA
authors.lastname: Lyons
authors.forename: A H
authors.initials: AH
authors.lastname: Mao
authors.forename: J R
authors.initials: JR
authors.lastname: Carlin
authors.forename: B V
authors.initials: BV
authors.lastname: Karanam
authors.forename: S H
authors.initials: SH
authors.lastname: Vincent
authors.forename: K
authors.initials: K
authors.lastname: Cheng
authors.forename: M T
authors.initials: MT
authors.lastname: Goulet
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism; D008253:Macaca mulatta; D023421:Models, Animal; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D007211:Indoles; D011966:Receptors, LHRH; D014363:Tryptamines; D007986:Luteinizing Hormone