Decahydroisoquinoline derivatives as novel non-peptidic, potent and subtype-selective somatostatin sst3 receptor antagonists

Starting from non-peptidic sst1-selective somatostatin receptor antagonists, first compounds with mixed sst1/sst3 affinity were identified by directed structural modifications. Systematic optimization of these initial leads afforded novel, enantiomerically pure, highly potent and sst3-subtype selective somatostatin antagonists based on a (4S,4aS,8aR)-decahydroisoquinoline-4-carboxylic acid core moiety. These compounds can efficiently be synthesized and show promising PK properties in rodents.

Graphical abstractStarting from non-peptidic sst1-selective somatostatin receptor antagonists, first compounds with mixed sst1/sst3 affinity were identified by directed structural modifications. Systematic optimization of these initial leads afforded novel, enantiomerically pure, highly potent and sst3-subtype selective somatostatin antagonists based on a (4S,4aS,8aR)-decahydro-isoquinoline-4-carboxylic acid core moiety. The representative compound ACQ090 can efficiently be synthesized and shows promising PK properties in rodents.Figure optionsDownload full-size imageDownload as PowerPoint slide