Lewis R T, Macleod A M, Merchant K J, Kelleher F, Sanderson I, Herbert R H, Cascieri M A, Sadowski S, Ball R G, Hoogsteen K
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Center, Harlow, Essex, U.K.
J Med Chem. 1995 Mar 17;38(6):923-33. doi: 10.1021/jm00006a011.
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 substance P receptor antagonist. A series of analogs which introduced a 6-membered heterocyclic ring into the backbone of this structure were prepared for evaluation as bioisosteric replacements of the ester linkage of 1. The 2,5-dioxopiperazine 2 had very weak receptor affinity, but 2-oxopiperazine 5 exhibited modest activity. Examination of the conformations accessible to the substituents on these templates led to exploration of the corresponding 5-membered heterocyclic rings. This study culminated in the identification of oxazolidinedione 14 as a suitable ester mimic in terms of the retention of good NK1 binding affinity.
