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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Nov 16

PMID 30429949

Citations 10

Authors

Weiguo Liu

Pengcheng P Shao

Gui-Bai Liang

John Bawiec

Jiafang He

Susan D Aster

Margaret Wu

Garry Chicchi

John Wang

Kwei-Lan Tsao

Jin Shang

Gino Salituro

Yun-Ping Zhou

Cai Li

Taro E Akiyama

Daniel E Metzger

Beth Ann Murphy

Andrew D Howard

Ann E Weber

Joseph L Duffy

Affiliations

Soon will be listed here.

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 , we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone emerged as a new highly potent and selective SSTR5 antagonist. Compound 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 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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