ABSTRACT
PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8B inhibition. Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE). These triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Diabetes Mellitus/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Animals , Cells, Cultured , Diabetes Mellitus/drug therapy , Drug Discovery , Enzyme Inhibitors/metabolism , High-Throughput Screening Assays , Humans , Insulin/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Ligands , Microsomes, Liver/metabolism , Protein Binding , Pyrimidines/metabolism , Rats , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/metabolism , Triazoles/pharmacologyABSTRACT
A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Piperidines/therapeutic use , Humans , Models, Molecular , Piperidines/chemistryABSTRACT
A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dogs , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of pyrrolidine based inhibitors of dipeptidyl peptidase IV were developed from a high throughput screening hit for the treatment of type 2 diabetes. Potency, selectivity, and pharmacokinetic properties were optimized resulting in the identification of a pre-clinical candidate for further profiling.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors , Fluorine/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Animals , Crystallography, X-Ray , Dipeptidyl Peptidase 4/chemistry , Dogs , Humans , Models, Molecular , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacokinetics , Rats , StereoisomerismABSTRACT
Inhibitors of the glucagon-like peptide-1 (GLP-1) degrading enzyme dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes in animal models and in human subjects. A novel series of cis-2,5-dicyanopyrrolidine alpha-amino amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. 1-({[1-(Hydroxymethyl)cyclopentyl]amino}acetyl)pyrrolidine-2,5-cis-dicarbonitrile (1c) is an achiral, slow-binding (time-dependent) inhibitor of DPP-IV that is selective for DPP-IV over other DPP isozymes and proline specific serine proteases, and which has oral bioavailability in preclinical species and in vivo efficacy in animal models. The mode of binding of the cis-2,5-dicyanopyrrolidine moiety was determined by X-ray crystallography. The hydrochloride salt of 1c was further profiled for development as a potential new treatment for type 2 diabetes.
Subject(s)
Adenosine Deaminase Inhibitors , Adenosine Deaminase/chemistry , Dipeptidyl Peptidase 4/chemistry , Glycoproteins/antagonists & inhibitors , Glycoproteins/chemistry , Hypoglycemic Agents/chemical synthesis , Nitriles/chemical synthesis , Pyrrolidines/chemical synthesis , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Dogs , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Injections, Intravenous , Male , Mice , Models, Molecular , Nitriles/chemistry , Nitriles/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Cyclohexylglycine amides of various fluorinated pyrrolidines and azetidines were prepared and tested for activity against dipeptidyl peptidase IV and in vivo in the KK mouse model of type 2 diabetes. The tetrafluoropyrrolidide, cis-3,4-difluoropyrrolidide and the fluorinated azetidides displayed unexpectedly strong activity.
Subject(s)
Adenosine Deaminase Inhibitors , Amides/chemical synthesis , Glycoproteins/antagonists & inhibitors , Pyrrolidines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Amides/pharmacology , Animals , Azetidines , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4 , Disease Models, Animal , Fluorine , Glucose Tolerance Test , Inhibitory Concentration 50 , Mice , Pyrrolidines/pharmacology , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The action of glucagon in the liver is mediated by G-coupled receptors. To examine the role of glucagon in glucose homeostasis, we have generated mice in which the glucagon receptor was inactivated (GR(-/-) mice). Blood glucose levels were somewhat reduced in GR(-/-) mice relative to wild type, in both the fed and fasted state. Plasma insulin levels were not significantly affected. There was no significant effect on fasting plasma cholesterol or triglyceride levels associated with deletion of the glucagon receptor. Glucose tolerance, as assessed by an oral glucose tolerance test, improved. Plasma glucagon levels were strikingly elevated in both fed and fasted animals. Despite a total absence of glucagon receptors, these animals maintained near-normal glycemia and normal lipidemia, in the presence of circulating glucagon concentrations that were elevated by two orders of magnitude.
