TRYPTOPHAN-DERIVED NK1 ANTAGONISTS - CONFORMATIONALLY CONSTRAINED HETEROCYCLIC BIOISOSTERES OF THE ESTER LINKAGE

The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 1 (L -732,138) has been identified previously as a potent and selective sub stance P receptor antagonist. A series of analogs which introduced a 6 -membered heterocyclic ring into the backbone of this structure were p repared for evaluation as bioisosteric replacements of the ester linka ge of 1. The 2,5-dioxopiperazine 2 had very weak receptor affinity, bu t 2-oxopiperazine 5 exhibited modest activity. Examination of the conf ormations accessible to the substituents on these templates led to exp loration of the corresponding 5-membered heterocyclic rings. This stud y culminated in the identification of oxazolidinedione 14 as a suitabl e ester mimic in terms of the retention of good NK1 binding affinity.