ABSTRACT
Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.
Subject(s)
Azetidines , Diabetes Mellitus, Type 2 , Hypoglycemia , Organophosphonates , Azetidines/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Glucokinase , Humans , Hypoglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Organophosphonates/pharmacology , Organophosphonates/therapeutic useABSTRACT
The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Catalytic Domain , Dipeptidases/antagonists & inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Indicators and Reagents , Isomerism , Kinetics , Models, Molecular , Solvents , Structure-Activity RelationshipABSTRACT
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemic Agents/chemical synthesis , Imidazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Catalytic Domain , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Mice , Mice, Obese , Models, Molecular , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Sodium Channel Blockers/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Several pyrazolo-, triazolo-, and imidazolopyrimidines were synthesized and evaluated as inhibitors of DPP4. Of these three classes of compounds, the imidazolopyrimidines displayed the greatest potency and demonstrated excellent selectivity over the other dipeptidyl peptidases. SAR evaluation for these scaffolds was described as they may represent potential treatments for type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Protease Inhibitors/chemical synthesis , Pyrimidines/chemistry , Dipeptidyl Peptidase 4/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Structure-Activity RelationshipABSTRACT
Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
