Graphical abstract A series of N-phenylnicotinamides (1–40) were designed and evaluated in vitro for their COX inhibitory activities. Most of the synthesized compounds were proved to be potent and selective inhibitors of COX-1. Compound 28 showed the most potent COX-1 inhibitory activity (COX-1 IC50=0.68±0.07μM) and good selectivity (COX-2 IC50>100μM). This compound may be useful as a lead compound for superior COX-1 inhibitors. On the basis of the biological results, structure–activity relationships for the COX-1-inhibitory activities of the synthesized N-phenylnicotinamides were discussed concisely.