We have established aromatic enamide-ene metathesis to give highly substituted indole derivatives. This is a new method for the preparation of chiral 2-trans-cyclopropyl indoles, which successfully led to our H4 antagonist candidates. Based on this findings, we also designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug-resistance indicated that NSAIDS modulation of multidrug resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.