title: Combinatorial solid phase synthesis of multiply substituted 1,4-benzodiazepines and affinity studies on the CCK2 receptor (part 1).
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 chole cys to kinin (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.
authors.affiliation: Pharmaceutical Sciences Research Institute, School of Life and Health Science, Aston University, Birmingham, United Kingdom. e.lattmann@aston.ac.uk
authors.forename: Eric
authors.initials: E
authors.lastname: Lattmann
authors.forename: David C
authors.initials: DC
authors.lastname: Billington
authors.forename: David R
authors.initials: DR
authors.lastname: Poyner
authors.forename: Pornthip
authors.initials: P
authors.lastname: Arayarat
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howitt
authors.forename: Spencer
authors.initials: S
authors.lastname: Lawrence
authors.forename: Michael
authors.initials: M
authors.lastname: Offel
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D006168:Guinea Pigs; D008297:Male; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000378:metabolism*
chemical_list: D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C468549:Bz-423