Tryptophan-Derived NK1 Antagonists: Conformationally Constrained Heterocyclic Bioisosteres of the Ester Linkage

Richard T. Lewis, Angus M. MacLeod, Kevin J. Merchant, Fintan Kelleher, Ian Sanderson, Richard H. Herbert, Margaret A. Cascieri, Sharon Sadowski, Richard G. Ball, Karst Hoogsteen

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)923-933
Number of pages11
JournalJournal of Medicinal Chemistry
Volume38
Issue number6
DOIs
Publication statusPublished - 1 Mar 1995
Externally publishedYes

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