STUDIES ON NEUROKININ ANTAGONISTS .4. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL DIPEPTIDE SUBSTANCE-P ANTAGONISTS - THYL-N-(PHENYLMETHYL)-3-(2-NAPHTHYL)-L-ALANINAMIDE AND ITS RELATED-COMPOUNDS

As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, syl]-N-met hyl-N-(phenylmethyl)-L-phenylalaninamide (2b). The lysine part in 2b w as first optimized to a (2S,4R)hydroxyproline derivative (3h),which is 2-fold more potent than 2b in [H-3]SP binding assay using guinea pig lung membranes. Next we modified the 1H-indol-3-ylcarbonyl part in 3h. Introduction; of a methyl group at the indole nitrogen enhanced the o ral activity, while retaining the binding activity. Finally, we modifi ed the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.