title: Pyrimido[4,5-d]azepines as potent and selective 5-HT2C receptor agonists: design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence.
abstract: New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK. mark.d.andrews@pfizer.com
authors.forename: Mark D
authors.initials: MD
authors.lastname: Andrews
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.forename: Tiffini K
authors.initials: TK
authors.lastname: Brabham
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.forename: Alison
authors.initials: A
authors.lastname: Bridgeland
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brown
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bungay
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Conlon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Edmunds
authors.forename: Kerry
authors.initials: K
authors.lastname: af Forselles
authors.forename: Colleen P
authors.initials: CP
authors.lastname: Gibbons
authors.forename: Martin P
authors.initials: MP
authors.lastname: Green
authors.forename: Giles
authors.initials: G
authors.lastname: Hanton
authors.forename: Mark
authors.initials: M
authors.lastname: Holbrook
authors.forename: Alan S
authors.initials: AS
authors.lastname: Jessiman
authors.forename: Karin
authors.initials: K
authors.lastname: McIntosh
authors.forename: Gordon
authors.initials: G
authors.lastname: McMurray
authors.forename: Carly L
authors.initials: CL
authors.lastname: Nichols
authors.forename: James A
authors.initials: JA
authors.lastname: Root
authors.forename: R Ian
authors.initials: RI
authors.lastname: Storer
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sutton
authors.forename: Robin V
authors.initials: RV
authors.lastname: Ward
authors.forename: Dominique
authors.initials: D
authors.lastname: Westbrook
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004285:Dogs; D008297:Male; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014549:Urinary Incontinence / Q000188:drug therapy
chemical_list: D001381:Azepines; C560210:PF 3246799; D011743:Pyrimidines; D058826:Serotonin 5-HT2 Receptor Agonists