Design, synthesis and biological evaluation of novel tricyclic cyclooxygenase-2 (COX-2) inhibitors

A diverse variety of novel classes of tricyclic compounds were designed, synthesized and evaluated using in vitro and in vivo pharmacological screens.; A diarylcycloalkyl class of compounds possessing a central three-membered cyclopropane ring (Chapter 1, 10--11) exhibited weak in vitro COX-2 inhibitory potency (3.0--214 muM range) and selectivity. In contrast, diarylheterocycles with a central six-membered pyran-2-one ring (Chapter 3, 14 and Chapter 4, 12) exhibited COX-2 inhibition in the 0.0032--415.8 muM range. Among the C-6 alkoxy substituted pyran-2-one class of compounds, 14i [6-ethoxy-3-(4-methanesulfonylphenyl)-4-(4-fluorophenyl)pyran-2-one] exhibited good in vitro COX-2 inhibitory potency and selectivity (COX-2 IC 50 = 0.10 muM; Selectivity Index = 2880) which parallels its in vivo antiinflammatory activity (32 and 67% reduction in inflammation at 3 and 5 h post-drug administration respectively for a 1 mg/kg oral dose). In vitro and in vivo assays for the pyranone class of compounds possessing a C-6 para-substituted-phenyl ring showed that they exhibit excellent biological activity profiles with compound 12e [6-(4-methoxyphenyl)-3-(4-methanesulfonyl phenyl)-4-phenylpyran-2-one] exhibiting a potent, selective COX-2 inhibition (COX-2 IC50 = 0.02 muM; Selectivity Index > 5000) and good antiinflammatory-analgesic activity.; Molecular modeling studies for the pyranone class of compounds revealed that substituents at the C-6 position of the central lactone ring influenced COX-2 inhibitory potency and selectivity by orienting the central ring such that the C-3 p-SO2Me COX-2 pharmacophore was in the vicinity of the COX-2 secondary pocket.; Results acquired in these investigations have shown that (i) a 3-membered cyclopropane ring can serve as a potential ring template for the design of tricyclic COX-2 inhibitors, (ii) a six-membered pyranone ring serves as a suitable central ring template for the design of diarylheterocyclic COX-2 inhibitors, (iii) the combined electronic and steric properties at the C-6 position of the central lactone ring modulate COX-2 inhibitory potency and selectivity by orienting the C-3 p-SO2Me phenyl substituent to the vicinity of the secondary pocket within the COX-2 binding site, and (iv) selective COX-2 inhibitors can be designed successfully using a rational drug design approach in conjunction with molecular modeling (docking) studies, chemical synthesis, and acquisition of structure activity relationship (SAR) data.