Selective Cyclooxygenase-2 Inhibitor Design, Synthesis And Three-dimensional Quantitative Structure-activity Relationship Studies,

Selective inhibitors of cyclooxygenase-2 (COX-2) are now widely recognized as offering the promise of treatment of inflammatory conditions without the side effects associated with classical non-steroid anti-inflammatory drugs (NSAIDs). Analyzing the structural feature of compounds with COX-2 inhibitory activity, we found that most of them possess two aryl rings in cisposition connecting with a third ring (including aryl ring, heterocycle, unsaturated aliphatic ring, et al.), and one of the two aromatic moieties being substituted at the para- position by a sulfonyl group.In order to get more structural information for designing new COX-2 inhibitors, COX-2 inhibitors that had been tested for the activity and selectivity were chosen to build two CoMFA model, using CoMFA (comparative molecular field analysis) method. Combining the electrostatic and steric standard coefficients contour map of these two models, more detailed structural information have been given: 1. Two aromatic rings should be monocycle; 2. In order to insure the positive electrical property for the aromatic ring without sulfonyl group, the substituted group's electrical property should be negative and small. To improve activity, the substituted group's bulk at para- position should be increased suitably, and to improve the selectivity, meta- position's bulk should be increased. 3. The substituted group's bulk should be increased suitably on the third ring. From all these characters of COX-2 inhibitors, new type of novel COX-2 inhibitors, substituted 3,4-diaryl-2,5(2H)-pyrrolin-2-ones, was designed and synthesized.To explore the effect of the position of sulfonylphenyl group relative to the α , β -unsaturated lactam carbonyl group on the activity and selectivity, its isomer was also synthesized respectively. Now, 38 compounds have been synthesized, and 30 compounds of series Ⅰ and Ⅱ have been tested for their biological active values (COX-1 and COX-2) on cell (thioglycollate elicited murine peritoneal macrophages) level, most of series Ⅰ compounds exhibit comparable inhibitory activity to Rofecoxib. Series Ⅱ compounds, however, show activities 10-100 times less than Rofecoxib. Most of series Ⅰ and Ⅱ exhibit good selectivity. QSAR directs further work.102 new products have been synthesized, of which 38 are target compounds. All these compounds have been identified by ~1H-NMR and EI-MS, some of them were by HR-MS and EA. In order to ensure the conformation of these compounds, a typical crystal, Bap-901 was analyzed X-ray crystallography.