ABSTRACT
For a series of beta-homophenylalanine based inhibitors of dipeptidyl peptidase IV ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
Subject(s)
Amides/chemistry , Aminobutyrates/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Structure-Activity Relationship , Amides/antagonists & inhibitors , Caco-2 Cells , Cell Line, Tumor , Chemistry, Pharmaceutical , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Design , Humans , Hypoglycemic Agents/antagonists & inhibitors , Hypoglycemic Agents/therapeutic use , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Sodium Channels/metabolismABSTRACT
A series of highly potent and selective inhibitors of DPP-4 was optimized for ADMET properties. The effort resulted in the discovery of inhibitor 1g, that exhibits excellent efficacy in an oral glucose tolerance test and an attractive pharmacokinetic profile.
Subject(s)
Aminobutyrates/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Hydrocarbons, Fluorinated/chemistry , Hypoglycemic Agents/chemistry , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Administration, Oral , Aminobutyrates/chemical synthesis , Aminobutyrates/pharmacokinetics , Animals , Caco-2 Cells , Cell Line, Tumor , Dipeptidyl Peptidase 4/metabolism , Dogs , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.
Subject(s)
Amides/chemical synthesis , Aminobutyrates/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Microsomes, Liver/drug effects , Sulfonamides/chemical synthesis , Amides/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Design , Glucagon-Like Peptide 1/antagonists & inhibitors , Hydrogen Bonding , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , Sulfonamides/pharmacologyABSTRACT
The co-crystal structure of beta-phenethylamine fragment inhibitor 5 bound to DPP-IV revealed that the phenyl ring occupied the proline pocket of the enzyme. This finding provided the basis for a general hypothesis of a reverse binding mode for beta-phenethylamine-based DPP-IV inhibitors. Novel inhibitor design concepts that obviate substrate-like structure-activity relationships (SAR) were thereby enabled, and novel, potent inhibitors were discovered.
