ABSTRACT
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Oxadiazoles/chemical synthesis , Animals , Diabetes Mellitus/drug therapy , Diacylglycerol O-Acyltransferase/metabolism , Dogs , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Ligands , Mice , Obesity/drug therapy , Oxadiazoles/pharmacokinetics , Quantitative Structure-Activity Relationship , RatsABSTRACT
A series of carboxylic acid glycogen phosphorylase inhibitors, which have potential as oral antidiabetic agents, is described. Defining and applying simple physicochemical design criteria was used to assess the opportunity and to focus synthetic efforts on compounds with the greatest probability of success. The study led to compound 17, which exhibits a good balance of properties including potent inhibition of recombinant human liver glycogen phosphorylase in vitro, a good DMPK profile including excellent bioavailability and low clearance and good in vivo activity in a glucagon challenge model of diabetes in Zucker rats.
Subject(s)
Carboxylic Acids/pharmacology , Glycogen Phosphorylase, Liver Form/antagonists & inhibitors , Hypoglycemic Agents/chemistry , Indans/pharmacology , Animals , Biological Availability , Carboxylic Acids/chemistry , Carboxylic Acids/therapeutic use , Drug Discovery , Humans , Hypoglycemic Agents/pharmacology , Indans/chemistry , Indans/therapeutic use , Rats , Rats, ZuckerABSTRACT
Two series of novel thienopyrrole inhibitors of recombinant human liver glycogen phosphorylase a (GPa) which are effective in reducing glucose output from rat hepatocytes are described. Representative compounds have been shown to bind at the dimer interface site of the rabbit muscle enzyme by X-ray crystallography.
