SYNTHESIS AND BIOLOGICAL EVALUATION OF NK1 ANTAGONISTS DERIVED FROM L-TRYPTOPHAN

The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan (3), which was derived from the screening lead N-ethyl-L-tryptophan benzyl ester, has been used as a starting point to identify high-affinity su bstance P receptor antagonists with improved in vivo activity. Alterin g the ester moiety to an amide or ether led to a substantial loss in b inding affinity, but conversion to a ketone provided compounds with af finity comparable to the equivalent esters. A homochiral synthesis of the key intermediate amino ketone 15 was developed which allows its pr eparation on a large scale. From this intermediate a range of amine-co ntaining acylamino derivatives were prepared with affinity optimized i n the morpholinylbutyramide 16l which has an IC50 of 0.17 nM at the hu man NK1 receptor. In addition to improving affinity, the amino group a lso provided aqueous solubility for a number of these derivatives. Whe n tested in. vivo the quinuclidine derivative L-737,488 (16i) was foun d to be an orally active (ID50 1.8 mg/kg) inhibitor of substance P-ind uced dermal extravasation in the guinea pig.