title: Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.
abstract: A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.
authors: Chemistry Department, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors: Guy
authors: G
authors: Rouquet
authors: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Groton Laboratories , Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Dianna E
authors: DE
authors: Moore
authors: Worldwide Medicinal Chemistry, and Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories , Sandwich, Kent CT13 9NJ, U.K.
authors: Malcolm
authors: M
authors: Spain
authors: Chemistry Department, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors: Daniel M
authors: DM
authors: Allwood
authors: Chemistry Department, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors: Claudio
authors: C
authors: Battilocchio
authors: Worldwide Medicinal Chemistry, and Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories , Sandwich, Kent CT13 9NJ, U.K.
authors: David C
authors: DC
authors: Blakemore
authors: Worldwide Medicinal Chemistry, and Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories , Sandwich, Kent CT13 9NJ, U.K.
authors: Paul V
authors: PV
authors: Fish
authors: Global Safety Pharmacology, Pfizer Global Research and Development , 10646 Science Center Drive, San Diego, California 92121, United States.
authors: Stephen
authors: S
authors: Jenkinson
authors: Worldwide Medicinal Chemistry, and Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories , Sandwich, Kent CT13 9NJ, U.K.
authors: Alan S
authors: AS
authors: Jessiman
authors: Chemistry Department, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors: Steven V
authors: SV
authors: Ley
authors: Worldwide Medicinal Chemistry, and Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories , Sandwich, Kent CT13 9NJ, U.K.
authors: Gordon
authors: G
authors: McMurray
authors: Worldwide Medicinal Chemistry, and Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories , Sandwich, Kent CT13 9NJ, U.K.
authors: R Ian
authors: RI
authors: Storer
keywords: 5-HT2C receptor agonist; CNS penetration; Tetrasubstituted pyridines; pyrido[3,4-d]azepine