Discovery of novel non-peptidic β-alanine piperazine amide derivatives and their optimization to achiral, easily accessible, potent and selective somatostatin sst1 receptor antagonists

Structural simplification of the core moieties of obeline and ergoline somatostatin sst1 receptor antagonists, followed by systematic optimization, led to the identification of novel, highly potent and selective sst1 receptor antagonists. These achiral, non-peptidic compounds are easily prepared and show promising PK properties in rodents.

Graphical abstractPharmacophore considerations based on obeline and ergoline somatostatin sst1 receptor antagonists led to the design of an achiral β-alanine piperazine amide derivative with largely retained sst1 affinity and selectivity. Systematic optimization of this initial hit afforded highly potent and selective sst1 receptor antagonists like fluorenyl derivative 22g or xanthenyl derivative 23. These achiral, non-peptidic compounds are easily prepared and show promising PK properties in rodents.Figure optionsDownload full-size imageDownload as PowerPoint slide