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Potent, orally absorbed glucagon receptor antagonists
S E de Laszlo1, C Hacker, B Li
1Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorganic & Medicinal Chemistry Letters
|April 14, 1999
Summary
Researchers investigated 2-pyridyl-3,5-diaryl pyrroles as inhibitors of p38 kinase and ligands of the human glucagon receptor. Compound 49 (L-168,049) was identified as a potent and selective glucagon receptor antagonist.
Area of Science:
- Medicinal Chemistry
- Pharmacology
Background:
- The human glucagon receptor (hGLR) plays a crucial role in glucose homeostasis.
- Inhibitors of p38 kinase are explored for various therapeutic applications.
- 2-pyridyl-3,5-diaryl pyrroles represent a chemical scaffold with potential biological activity.
Purpose of the Study:
- To investigate the structure-activity relationship (SAR) of 2-pyridyl-3,5-diaryl pyrroles.
- To identify potent and selective ligands for the human glucagon receptor.
- To explore the potential of these compounds as inhibitors of p38 kinase.
Main Methods:
- Synthesis of a library of 2-pyridyl-3,5-diaryl pyrrole derivatives.
- In vitro assays to determine binding affinity (Kb) to the human glucagon receptor.
- Evaluation of selectivity against other related receptors.
- Assessment of p38 kinase inhibitory activity.
Main Results:
- The SAR study led to the identification of compound 49 (L-168,049).
- Compound 49 demonstrated potent binding to the human glucagon receptor with a Kb of 25 nM.
- Compound 49 exhibited high selectivity as a glucagon receptor antagonist.
Conclusions:
- 2-pyridyl-3,5-diaryl pyrroles are a promising class of compounds for targeting the glucagon receptor.
- Compound 49 (L-168,049) is a highly potent and selective antagonist of the human glucagon receptor.
- Further investigation into the therapeutic potential of compound 49 is warranted.