posted on 2007-01-11, 00:00authored byJesper Lau, Carsten Behrens, Ulla G. Sidelmann, Lotte B. Knudsen, Behrend Lundt, Christian Sams, Lars Ynddal, Christian L. Brand, Lone Pridal, Anthony Ling, Dan Kiel, Michael Plewe, Shengua Shi, Peter Madsen
A weak human glucagon receptor antagonist with an IC50 of 7 μM was initially found by screening of
libraries originally targeted to mimic the binding of the glucagon-like peptide (GLP-1) hormone to its receptor.
Optimization of this hit for binding affinity for the glucagon receptor led to ligands with affinity in the
nanomolar range. In addition to receptor binding, optimization efforts were made to stabilize the molecules
against fast metabolic turnover. A potent antagonist of the human human glucagon receptor was obtained
that had 17% oral availability in rats with a plasma half-life of 90 min. The major metabolites of this lead
were identified and used to further optimize this series with respect to pharmacokinetic properties. This
final optimization led to a potent glucagon antagonist that was orally available in rats and dogs and was
efficacious in lowering blood glucose levels in a diabetic animal model.