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Discovery of N-aryl-2-acylindole human glucagon receptor antagonists.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Dec 01; Vol. 21 (23), pp. 7124-30. Date of Electronic Publication: 2011 Oct 05. - Publication Year :
- 2011
-
Abstract
- A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Diabetes Mellitus, Type 2 drug therapy
Dogs
Humans
Indoles chemistry
Mice
Mice, Transgenic
Molecular Structure
Structure-Activity Relationship
Blood Glucose drug effects
Drug Discovery
Hypoglycemic Agents chemical synthesis
Hypoglycemic Agents chemistry
Hypoglycemic Agents pharmacology
Indoles chemical synthesis
Indoles pharmacology
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 :
- 22030028
- Full Text :
- https://doi.org/10.1016/j.bmcl.2011.09.105