Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor

A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. An SAR exploration of the lead class resulted in 13, which exhibited good potency as an hGCGR functional antagonist (IC 50 = 34 nM) and moderate bioavailability (36% in mice). A novel class of antagonists of the...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 15; no. 5; pp. 1401 - 1405
Main Authors:	Duffy, Joseph L., Kirk, Brian A., Konteatis, Zenon, Campbell, Elizabeth L., Liang, Rui, Brady, Edward J., Candelore, Mari Rios, Ding, Victor D.H., Jiang, Guoqiang, Liu, Frank, Qureshi, Sajjad A., Saperstein, Richard, Szalkowski, Deborah, Tong, Sharon, Tota, Lauri M., Xie, Dan, Yang, Xiaodong, Zafian, Peter, Zheng, Song, Chapman, Kevin T., Zhang, Bei B., Tata, James R.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-03-2005 Elsevier
Subjects:	Biological and medical sciences Diabetes General and cellular metabolism. Vitamins Gewald Glucagon Hormones. Endocrine system Humans Medical sciences Molecular Structure Pharmacology. Drug treatments Receptors, Glucagon - antagonists & inhibitors Structure-Activity Relationship Thiophene Thiophenes - chemical synthesis Thiophenes - classification Thiophenes - pharmacology Diabetes Thiophene Glucagon Gewald Five membered ring Nitrile Intravenous administration Thiophene derivatives Hypoglycemic agent Structure activity relation Chlorine Organic compounds Antagonist Chemical synthesis Oxygen nitrogen heterocycle Human Rodentia Oral administration Bioavailability In vitro In vivo Vertebrata Sulfur heterocycle Mammalia Mouse Animal Carboxamide Pharmacokinetics Hormonal receptor
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Summary:	A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. An SAR exploration of the lead class resulted in 13, which exhibited good potency as an hGCGR functional antagonist (IC 50 = 34 nM) and moderate bioavailability (36% in mice). A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC 50 = 34 nM) and moderate bioavailability (36% in mice).
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2005.01.003