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The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

Abstract：

:We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Shaghafi MB,Barrett DG,Willard FS,Overman LE

doi

10.1016/j.bmcl.2014.01.021

subject

Has Abstract

pub_date

2014-02-15 00:00:00

pages

1031-6

issue

4

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(14)00040-7

journal_volume

24

pub_type

杂志文章

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