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Discovery of cyclic guanidines as potent, orally active, human glucagon receptor antagonists.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Dec 01; Vol. 21 (23), pp. 7131-6. Date of Electronic Publication: 2011 Sep 29. - Publication Year :
- 2011
-
Abstract
- In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Cyclization
Diabetes Mellitus, Type 2 drug therapy
Disease Models, Animal
Dogs
Guanidines chemistry
Guanidines pharmacology
Humans
Hypoglycemic Agents chemical synthesis
Hypoglycemic Agents chemistry
Hypoglycemic Agents pharmacology
Inhibitory Concentration 50
Molecular Structure
Rats
Structure-Activity Relationship
Blood Glucose drug effects
Drug Discovery
Guanidines chemical synthesis
Receptors, Glucagon antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 21
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 22001094
- Full Text :
- https://doi.org/10.1016/j.bmcl.2011.09.085