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

Lattmann, Eric, Billington, David C., Poyner, David R., Arayarat, Pornthip, Howitt, Stephen B., Lawrence, Spencer and Offel, Michael (2002). Combinatorial solid phase synthesis of multiply substituted 1,4-benzodiazepines and affinity studies on the CCK2 receptor (Part 1). Drug Design and Discovery, 18 (1), pp. 9-21.

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.

Publication DOI: https://doi.org/10.1080/10559610213504
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Additional Information: Journal title now changed to "Drug development and industrial pharmacy"
Uncontrolled Keywords: 1,4-benzodiazepine template,CCK-antagonists,cholecystokinin,combinatorial chemistry,lead structure,receptor binding,solid phase synthesis,syn-phase crowns,Molecular Medicine,Drug Discovery
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2002-12
Authors: Lattmann, Eric
Billington, David C.
Poyner, David R. ( 0000-0003-1590-112X)
Arayarat, Pornthip
Howitt, Stephen B.
Lawrence, Spencer
Offel, Michael

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