Rational design of 6-methylsulfonylindoles as selective cyclooxygenase-2 inhibitors.
The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.
Campbell
Jeffrey A
JA
Roche Palo Alto, 3431 Hillview Ave, Palo Alto, CA 94304, USA. jcampbell@ptcbio.com
Bordunov
Viola
V
Broka
Chris A
CA
Browner
Michelle F
MF
Kress
James M
JM
Mirzadegan
Tara
T
Ramesha
Chakk
C
Sanpablo
Bong F
BF
Stabler
Russell
R
Takahara
Patricia
P
Villasenor
Armando
A
Walker
Keith A M
KA
Wang
Jin-Hai
JH
Welch
Mary
M
Weller
Paul
P
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D008565:Membrane Proteins; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D008565:Membrane Proteins; D013450:Sulfones; D002351:Carrageenan; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases