Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists
2018
A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective
somatostatin receptorsubtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profiles compared to those of the original
lead compound1 while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue 13 demonstrated efficacy in a mouse oral
glucose tolerance testand an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies. In this Communication, we discuss the relationship among structure, in vitro and in vivo activity, metabolic stability, and ultimately the potential of these compounds as therapeutic agents for the treatment of type 2 diabetes. Furthermore, we show how the use of focused libraries significantly expanded the structural class and provided new directions for structure–activity relationship optimization.
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