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

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

ACS medicinal chemistry letters, 08 November 2018, Vol.9(11), pp.1088-1093 [Peer Reviewed Journal]

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  • Title:
    Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists
  • Author: 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
  • Description: 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 while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue 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.
  • Is Part Of: ACS medicinal chemistry letters, 08 November 2018, Vol.9(11), pp.1088-1093
  • Identifier: ISSN: 1948-5875 ; PMID: 30429950 Version:1 ; DOI: 10.1021/acsmedchemlett.8b00306
  • Language: English

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