Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity.
Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.
Lazer
E S
ES
Department of Inflammatory Disease, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, connecticut 06877, USA.
Miao
C K
CK
Cywin
C L
CL
Sorcek
R
R
Wong
H C
HC
Meng
Z
Z
Potocki
I
I
Hoermann
M
M
Snow
R J
RJ
Tschantz
M A
MA
Kelly
T A
TA
McNeil
D W
DW
Coutts
S J
SJ
Churchill
L
L
Graham
A G
AG
David
E
E
Grob
P M
PM
Engel
W
W
Meier
H
H
Trummlitz
G
G
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D000077239:Meloxicam; D008565:Membrane Proteins; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011994:Recombinant Proteins; D013843:Thiazines; D013844:Thiazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077239:Meloxicam