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%.
|Number of pages||12|
|Journal||Drug Design and Discovery|
|Publication status||Published - 25 Jul 2001|
- guinea pigs
- male receptors
- cholecystokinin structure-activity relationship
Lattmann, E., Billington, D. C., Poyner, D., Howitt, S. B., & Offel, M. (2001). Synthesis and evaluation of asperlicin analogues as non-peptidal cholecystokinin-antagonists. Drug Design and Discovery, 17(3), 219-230.