Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists
| Autor: | Weiguo Liu, Ramzi F. Sweis, Feroze Ujjainwalla, Remond Moningka, F. Anthony Romero, Yi Zang, Paul E. Finke, Zahid Hussain, Karen H. Dingley, Michael A. Plotkin, Andrew D. Howard, Jin Shang, Beth Ann Murphy, Jianming Bao, Gino Salituro, Harold B. Wood, Joseph L. Duffy |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Somatostatin receptor Chemistry Organic Chemistry 030209 endocrinology & metabolism Metabolism Pharmacology Biochemistry In vitro 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Somatostatin Pharmacokinetics In vivo Pharmacodynamics Drug Discovery Lead compound |
| Zdroj: | ACS Medicinal Chemistry Letters. 9:1088-1093 |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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