Identification and optimisation of a novel series of pyrimidine based cyclooxygenase-2 (COX-2) inhibitors. Utilisation of a biotransformation approach.
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.
Beswick
Paul J
PJ
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
Blackaby
Andrew P
AP
Bountra
Chas
C
Brown
Terry
T
Browning
Kerry
K
Campbell
Ian B
IB
Corfield
John
J
Gleave
Robert J
RJ
Guntrip
Steve B
SB
Hall
Richard M
RM
Hindley
Sean
S
Lambeth
Paul F
PF
Lucas
Fiona
F
Mathews
Neil
N
Naylor
Alan
A
Player
Hazel
H
Price
Helen S
HS
Sidebottom
Phillip J
PJ
Taylor
Nicholas L
NL
Webb
Graham
G
Wiseman
Joanne
J
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
D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2