Antiinflammatory 4,5-Diarylpyrroles. 2. Activity as a Function of Cyclooxygenase-2 Inhibition

Abstract

The antiinflammatory activity of a series of 2-substituted- and 2,3-disubstituted-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H- pyrroles was previously shown by quantitative structure-activity relationship (QSAR) studies to be correlated with the molar refractivity and inductive field effect of the 2-substituent and the lipophilicity of the 3-substituent. The present study demonstrates that much of the antiinflammatory activity of these pyrroles could be correlated with the inhibition of the inducible isoform of cyclooxygenase (COX2). Additional QSAR studies have been used to identify the molecular parameters necessary for maximizing COX2 inhibition while simultaneously minimizing the inhibition of constitutively expressed cyclooxygenase-1. Such an effort should facilitate the discovery and development of selective COX inhibitors that should lead to safer nonsteroidal antiinflammatory drugs.

Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4′-isomer

“…These results are in agreement with structure-activity relationship studies performed previously within the class of the enol-caroxamids [22] and within other chemical classes [23][24][25]. The steric position of the methyl group in Mel may be the reason for the less potent binding to COX-1 in comparison to COX-2.…”

Structural diversity of selective COX-2 inhibitors

“…5) and pyridines reveals that substitution other than in the 1-or 2-position in the central benzene ring in terphenyls with groups as small as fluorine affords inactive compounds, whereas such replacements are not problematic in the pyridine series as indicated with etoricoxib in Figure 6. SAR studies on diarylpyrroles indicate that COX-2 can be selectively inhibited by all possible isomers (l,2-diaryl, 2,3-diaryl and 3,4-diaryl) [59][60][61]. Furthermore, regardless of the 4-methylsulfonylphenyl-substitution pattern (Nl versus C-2), the l,2-diarylpyrrole regioisomers maintained selective COX-2 inhibitory properties (see Fig.…”

“…Examples of central heterocycles include 5-or 6-membered rings that contain one (thiophenes [35][36][37], pyrroles [59][60][61], furans [62,63] and pyridines Pyrroles Eurans 2(5H)-Furanones Thiazo1es 21 [64][65][66]), two (thiazoles [67,68], oxazoles and the corresponding oxazolones [69,70], imidazoles [71][72][73], isoxazoles [74][75][76], pyrazoles [38,[77][78][79]), or three (thiadiazole [80]) heteroatoms (Fig. 6).…”

Synthesis of novel 3,4‐diaryl‐1H‐pyrroles

“…Previously, 4,5-diarylpyrroles having phenyl sulfone substituent have been known as anti-inflammatory drugs and COX-2 inhibitors [4]. In continuation of our research program dealing with the syntheses of 1,2-diaryl five membered heterocycles [5][6][7][8] anti-inflammatory drug.…”