Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Swarbrick
Martin E
ME
Pain and Neuroexcitability Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Beswick
Paul J
PJ
Gleave
Robert J
RJ
Green
Richard H
RH
Bingham
Sharon
S
Bountra
Chas
C
Carter
Malcolm C
MC
Chambers
Laura J
LJ
Chessell
Iain P
IP
Clayton
Nick M
NM
Collins
Sue D
SD
Corfield
John A
JA
Hartley
C David
CD
Kleanthous
Savvas
S
Lambeth
Paul F
PF
Lucas
Fiona S
FS
Mathews
Neil
N
Naylor
Alan
A
Page
Lee W
LW
Payne
Jeremy J
JJ
Pegg
Neil A
NA
Price
Helen S
HS
Skidmore
John
J
Stevens
Alexander J
AJ
Stocker
Richard
R
Stratton
Sharon C
SC
Stuart
Alastair J
AJ
Wiseman
Joanne O
JO
D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods; D051546:Cyclooxygenase 2 / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D004987:Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology
D000588:Amines; D052246:Cyclooxygenase 2 Inhibitors; D004987:Ethers; D011743:Pyrimidines; D013450:Sulfones; D051546:Cyclooxygenase 2