The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus

A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glu...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (10), p.3051-3058
Main Authors: Guzman-Perez, Angel, Pfefferkorn, Jeffrey A., Lee, Esther C.Y., Stevens, Benjamin D., Aspnes, Gary E., Bian, Jianwei, Didiuk, Mary T., Filipski, Kevin J., Moore, Dianna, Perreault, Christian, Sammons, Matthew F., Tu, Meihua, Brown, Janice, Atkinson, Karen, Litchfield, John, Tan, Beijing, Samas, Brian, Zavadoski, William J., Salatto, Christopher T., Treadway, Judith
Format: Article
Language:English
Subjects:
Animals
antagonists
bioavailability
Chemistry, Physical
cytotoxicity
Diabetes mellitus
Diabetes Mellitus, Type 2 - drug therapy
Dogs
Dose-Response Relationship, Drug
Drug Design
Epithelial Cells - drug effects
glucagon
Glucagon receptor antagonist
glucagon receptors
glucose
Haplorhini
Humans
hydrophobicity
Liver - cytology
Mice
Molecular Structure
molecular weight
noninsulin-dependent diabetes mellitus
pharmacokinetics
Physicochemical properties
Propionates - administration & dosage
Propionates - chemical synthesis
Propionates - pharmacology
propionic acid
Rats
Receptors, Glucagon - antagonists & inhibitors
screening
Small Molecule Libraries - administration & dosage
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
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Summary:A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.03.014