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 2005-03, Vol.15 (5), p.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: Article
Language:English
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
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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).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.01.003