Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5‑Selective Antagonists

• Published in: ACS medicinal chemistry letters Vol. 9; no. 11; pp. 1088 - 1093
• Main Authors: Liu, Weiguo, Hussain, Zahid, Zang, Yi, Sweis, Ramzi F, Romero, F. Anthony, Finke, Paul E, Moningka, Remond, Bao, Jianming, Plotkin, Michael A, Shang, Jin, Dingley, Karen H, Salituro, Gino, Murphy, Beth Ann, Howard, Andrew D, Ujjainwalla, Feroze, Wood, Harold B, Duffy, Joseph L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.11.2018; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Glucose-dependent insulin secretion (GDIS); Metabolic stability; Somatostatin; Type 2 diabetes mellitus (T2DM); SSTR5 antagonists; POTENT; GLP-1; SSTRS antagonists; 5 SSTR5 ANTAGONISTS; DISCOVERY
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.8b00306

A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 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 compound 1 while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue 13 demonstrated efficacy in a mouse oral glucose tolerance test and 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.