title: Synthesis and evaluation of asperlicin analogues as non-peptidal cholecystokinin-antagonists.
abstract: The SAR of Asperlicin analogues is reported, leading to bioactive 1,4-benzodiazepine-2-ones, which were prepared in a 3 step reaction sequence. The Asperlicin substructure was built up using Tryptophan and readily available 2-amino-acetophenones. This template, containing a 1,4-benzodiazepin-2-one moiety with a 3-indolmethyl side chain, was transformed into mono- and di-substituted 3-indol-3'-yl-methyl-1,4-benzodi-azepine-2-ones by selective alkylation and acylation reactions. The SAR optimization of the 1,4-benzodiazepine scaffold has included variations at the 5-, 7-, 8-position, at the N1, N-indole nitrogen and the configuration of the C3-position. The most active Asperlicin analogue, having an IC50 of 1.6 microM on the CCKA receptor subtype, was obtained from Tryptophan in only 3 steps in an overall yield of 48%.
authors.affiliation: Pharmaceutical Sciences Research Institute, School of Life and Health Sciences, Aston University, Birmingham, UK. e.lattmann@aston.ac.uk
authors.forename: E
authors.initials: E
authors.lastname: Lattmann
authors.forename: D C
authors.initials: DC
authors.lastname: Billington
authors.forename: D R
authors.initials: DR
authors.lastname: Poyner
authors.forename: S B
authors.initials: SB
authors.lastname: Howitt
authors.forename: M
authors.initials: M
authors.lastname: Offel
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D008297:Male; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001570:Benzodiazepinones; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin; C046367:asperlicin