2. Academic Validation
  3. Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition

Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition

  • ACS Med Chem Lett. 2018 Sep 12;9(11):1082-1087. doi: 10.1021/acsmedchemlett.8b00305.
Weiguo Liu 1,  Pengcheng P Shao 1,  Gui-Bai Liang 1,  John Bawiec 1,  Jiafang He 1,  Susan D Aster 1,  Margaret Wu 1,  Garry Chicchi 1,  John Wang 1,  Kwei-Lan Tsao 1,  Jin Shang 1,  Gino Salituro 1,  Yun-Ping Zhou 1,  Cai Li 1,  Taro E Akiyama 1,  Daniel E Metzger 1,  Beth Ann Murphy 1,  Andrew D Howard 1,  Ann E Weber 1,  Joseph L Duffy 1
Affiliations

Affiliation

  • 1 Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
PMID: 30429949 DOI: 10.1021/acsmedchemlett.8b00305
Abstract

We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 Antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 Antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 Inhibitor, substantially increasing circulating active GLP-1[7-36] amide and Insulin in response to a glucose challenge.

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