title: Identification and optimisation of a novel series of pyrimidine based cyclooxygenase-2 (COX-2) inhibitors. Utilisation of a biotransformation approach.
abstract: Many years of work have been invested in the identification of potent and selective COX-2 inhibitors for the treatment of chronic inflammatory pain. One issue faced by workers is the balance between the lipophilicity required for potent enzyme inhibition and the physical properties necessary for drug absorption and distribution in vivo. Frequently approaches to reduce lipophilicity through introduction of polar functionality is hampered by highly challenging chemistry to prepare key molecules. We have complemented traditional synthetic chemistry with a biotransformations approach which efficiently provided access to an array of key target molecules.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Beswick
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Blackaby
authors.forename: Chas
authors.initials: C
authors.lastname: Bountra
authors.forename: Terry
authors.initials: T
authors.lastname: Brown
authors.forename: Kerry
authors.initials: K
authors.lastname: Browning
authors.forename: Ian B
authors.initials: IB
authors.lastname: Campbell
authors.forename: John
authors.initials: J
authors.lastname: Corfield
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gleave
authors.forename: Steve B
authors.initials: SB
authors.lastname: Guntrip
authors.forename: Richard M
authors.initials: RM
authors.lastname: Hall
authors.forename: Sean
authors.initials: S
authors.lastname: Hindley
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambeth
authors.forename: Fiona
authors.initials: F
authors.lastname: Lucas
authors.forename: Neil
authors.initials: N
authors.lastname: Mathews
authors.forename: Alan
authors.initials: A
authors.lastname: Naylor
authors.forename: Hazel
authors.initials: H
authors.lastname: Player
authors.forename: Helen S
authors.initials: HS
authors.lastname: Price
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Sidebottom
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Taylor
authors.forename: Graham
authors.initials: G
authors.lastname: Webb
authors.forename: Joanne
authors.initials: J
authors.lastname: Wiseman
mesh_terms: D001711:Biotransformation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D051546:Cyclooxygenase 2 / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2