title: New beta-alanine derivatives are orally available glucagon receptor antagonists.
abstract: A weak human glucagon receptor antagonist with an IC50 of 7 microM 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.
authors.affiliation: Protein Engineering, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. jela@novonordisk.com
authors.forename: Jesper
authors.initials: J
authors.lastname: Lau
authors.forename: Carsten
authors.initials: C
authors.lastname: Behrens
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Sidelmann
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: Behrend
authors.initials: B
authors.lastname: Lundt
authors.forename: Christian
authors.initials: C
authors.lastname: Sams
authors.forename: Lars
authors.initials: L
authors.lastname: Ynddal
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Lone
authors.initials: L
authors.lastname: Pridal
authors.forename: Anthony
authors.initials: A
authors.lastname: Ling
authors.forename: Dan
authors.initials: D
authors.lastname: Kiel
authors.forename: Michael
authors.initials: M
authors.lastname: Plewe
authors.forename: Shengua
authors.initials: S
authors.lastname: Shi
authors.forename: Peter
authors.initials: P
authors.lastname: Madsen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004285:Dogs; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D015091:beta-Alanine