Combinatorial solid phase synthesis of multiply substituted 1,4-benzodiazepines and affinity studies on the CCK2 receptor (Part 1)

Eric Lattmann*, David C. Billington, David R. Poyner, Pornthip Arayarat, Stephen B. Howitt, Spencer Lawrence, Michael Offel

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

One hundred sixty-eight multiply substituted 1,4-benzodiazepines have been prepared by a five-step solid-phase combinatorial approach using syn-phase crowns as a solid support and a hydroxymethyl-phenoxy-acetamido linkage (Wang linker). The substituents of the 1,4-benzodiazepine scaffold have been varied in the -3, -5, -7, and 8-positions and the combinatorial library was evaluated in a cholecystokinin (CCK) radioligand binding assay. 3-Alkylated 1,4-benzodiazepines with selectivity towards the CCK-B (CCK2) receptor have been optimized on the lipophilic side chain, the ketone moiety, and the stereochemistry at the 3-position. Various novel 3-alkylated compounds were synthesized and [S]3-propyl-5-phenyl-1,4-benzodiazepin-2-one, [S]NV-A, has shown a CCK-B selective binding at about 180 nM. Fifty-eight compounds of this combinatorial library were purified by preparative TLC and 25 compounds were isolated and fully characterized by TLC, IR, APCI-MS, and 1H/13C-NMR spectroscopy.

Original languageEnglish
Pages (from-to)9-21
Number of pages13
JournalDrug Design and Discovery
Volume18
Issue number1
DOIs
Publication statusPublished - Dec 2002

Bibliographical note

Journal title now changed to "Drug development and industrial pharmacy"

Keywords

  • 1,4-benzodiazepine template
  • CCK-antagonists
  • cholecystokinin
  • combinatorial chemistry
  • lead structure
  • receptor binding
  • solid phase synthesis
  • syn-phase crowns

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