title: Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.
abstract: The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.
authors: Pfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich Kent CT139NJ, UK.
authors: Patrick S
authors: PS
authors: Johnson
authors: Thomas
authors: T
authors: Ryckmans
authors: Justin
authors: J
authors: Bryans
authors: Dave M
authors: DM
authors: Beal
authors: Kevin N
authors: KN
authors: Dack
authors: Neil
authors: N
authors: Feeder
authors: Anthony
authors: A
authors: Harrison
authors: Mark
authors: M
authors: Lewis
authors: Helen J
authors: HJ
authors: Mason
authors: James
authors: J
authors: Mills
authors: Julie
authors: J
authors: Newman
authors: Christelle
authors: C
authors: Pasquinet
authors: Dave J
authors: DJ
authors: Rawson
authors: Lee R
authors: LR
authors: Roberts
authors: Rachel
authors: R
authors: Russell
authors: Deborah
authors: D
authors: Spark
authors: Alan
authors: A
authors: Stobie
authors: Toby J
authors: TJ
authors: Underwood
authors: Robin
authors: R
authors: Ward
authors: Simon
authors: S
authors: Wheeler
mesh_terms: D065092:Antidiuretic Hormone Receptor Antagonists; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015195:Drug Design; D055808:Drug Discovery; D004355:Drug Stability; D004412:Dysmenorrhea / Q000188:drug therapy*; D005260:Female; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008861:Microsomes / Q000502:physiology; D015394:Molecular Structure; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D006727:Hormone Antagonists; C571353:PF-184563; D014230:Triazoles; D001569:Benzodiazepines; D003577:Cytochrome P-450 Enzyme System