ABSTRACT
AIMS: Since 2006, DPP-4 inhibitors have become established therapy for the treatment of type 2 diabetes. Despite sharing a common mechanism of action, considerable chemical diversity exists amongst members of the DPP-4 inhibitor class, raising the question as to whether structural differences may result in differentiated enzyme inhibition and antihyperglycaemic activity. METHODS: We have compared the binding properties of the most commonly used inhibitors and have investigated the relationship between their inhibitory potency at the level of the enzyme and their acute glucose-lowering efficacy. RESULTS: Firstly, using a combination of published crystal structures and in-house data, we demonstrated that the binding site utilized by all of the DPP-4 inhibitors assessed was the same as that used by neuropeptide Y, supporting the hypothesis that DPP-4 inhibitors are able to competitively inhibit endogenous substrates for the enzyme. Secondly, we ascertained that the enzymatic cleft of DPP-4 is a relatively large cavity which displays conformational flexibility to accommodate structurally diverse inhibitor molecules. Finally, we found that for all inhibitors, irrespective of their chemical structure, the inhibition of plasma DPP-4 enzyme activity correlates directly with acute plasma glucose lowering in mice. CONCLUSION: The common binding site utilized by different DPP-4 inhibitors enables similar competitive inhibition of the cleavage of the endogenous DPP-4 substrates. Furthermore, despite chemical diversity and a range of binding potencies observed amongst the DPP-4 inhibitors, a direct relationship between enzyme inhibition in the plasma and glucose lowering is evident in mice for each member of the classes studied.
ABSTRACT
Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Discovery , Pyrrolidines/pharmacology , Animals , Crystallography, X-Ray , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dogs , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.
Subject(s)
Amides/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Pyrans/chemistry , Sulfonamides/chemistry , Animals , Binding Sites , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Dogs , Half-Life , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Molecular Docking Simulation , Protein Structure, Tertiary , Pyrans/chemical synthesis , Pyrans/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Pyrans/chemical synthesis , Animals , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Enzyme Activation/drug effects , Glucose Tolerance Test , Haplorhini , Humans , Inhibitory Concentration 50 , Pyrans/chemistry , Pyrans/pharmacology , Rats , StereoisomerismABSTRACT
A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.
Subject(s)
Cyclohexanes/chemical synthesis , Cyclohexanes/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , Biological Availability , Cyclohexanes/pharmacokinetics , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Half-Life , Piperidines/pharmacokinetics , RatsABSTRACT
A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
Subject(s)
Chemistry, Pharmaceutical/methods , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Piperidines/chemistry , Piperidines/chemical synthesis , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Crystallography, X-Ray/methods , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Drug Design , Glucagon-Like Peptide 1/chemistry , Humans , Hydrolysis , Imidazoles/pharmacology , Inhibitory Concentration 50 , Macaca mulatta , Mice , Piperidines/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Sitagliptin Phosphate , Triazoles/chemical synthesis , Triazoles/pharmacologyABSTRACT
The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
Subject(s)
Alkenes/pharmacokinetics , Amides/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Hydrocarbons, Fluorinated/pharmacokinetics , Hypoglycemic Agents/pharmacokinetics , Microsomes, Liver/drug effects , Alkenes/chemical synthesis , Animals , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Hydrocarbons, Fluorinated/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Microsomes, Liver/pathology , Models, Chemical , Molecular Mimicry , Rats , Stereoisomerism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
Subject(s)
Amides/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors , Piperazines/chemical synthesis , Pyrazines/chemical synthesis , Triazoles/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Animals , Crystallography, X-Ray , Dipeptidyl Peptidase 4/chemistry , Dogs , Glucose Tolerance Test , Haplorhini , Humans , Male , Mice , Mice, Inbred C57BL , Piperazines/pharmacokinetics , Piperazines/pharmacology , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
A series of substituted imidazopiperidine amides has been prepared and evaluated for inhibition of dipeptidyl peptidase IV (DPP-4). Substitution at the 1- and 3-positions produced increased selectivity for DPP-4 relative to DPP-8 and DPP-9. Compounds in this series had IC(50) values as low as 5.8 nM for inhibition of DPP-4.
Subject(s)
Diabetes Mellitus/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemic Agents/pharmacology , Piperidines/pharmacology , Protease Inhibitors/pharmacology , Amides/chemistry , Humans , Hypoglycemic Agents/therapeutic use , Piperidines/chemistry , Piperidines/therapeutic use , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic useABSTRACT
A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
Subject(s)
Alanine/analogs & derivatives , Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/pharmacology , Administration, Oral , Alanine/chemistry , Alanine/pharmacology , Animals , Area Under Curve , Mice , Models, Molecular , Protease Inhibitors/administration & dosage , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokineticsABSTRACT
Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.
Subject(s)
Amides/chemistry , Amides/pharmacology , Dipeptidyl-Peptidase IV Inhibitors , Piperazines/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Models, Molecular , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , RatsABSTRACT
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Animals , Area Under Curve , Biological Availability , Half-Life , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Molecular Structure , Piperidines/blood , Rats , Structure-Activity RelationshipABSTRACT
Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/pharmacology , Pyrimidines/pharmacology , Drug Design , Models, Molecular , Protease Inhibitors/chemistry , Pyrimidines/chemistry , Quantitative Structure-Activity RelationshipABSTRACT
A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.
Subject(s)
Amides/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Piperazines/chemistry , Protease Inhibitors/pharmacology , Pyrazines/pharmacology , Triazoles/chemistry , Animals , Protease Inhibitors/chemical synthesis , Pyrazines/chemistry , Rats , Sitagliptin Phosphate , Structure-Activity Relationship , Triazoles/pharmacologyABSTRACT
A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment. The X-ray crystal structure of 25 bound to the DPP-4 active site is presented.
Subject(s)
Alanine/analogs & derivatives , Cyclohexanes/pharmacology , Dipeptidyl-Peptidase IV Inhibitors , Enzyme Inhibitors/pharmacology , Phenylalanine/analogs & derivatives , Administration, Oral , Alanine/chemistry , Alanine/pharmacology , Animals , Binding Sites , Biological Availability , Crystallography, X-Ray , Cyclohexanes/chemistry , Dipeptidyl Peptidase 4/chemistry , Enzyme Inhibitors/chemistry , Glucose Tolerance Test , Mice , Models, Molecular , Molecular Structure , Phenylalanine/chemistry , Phenylalanine/pharmacology , Structure-Activity RelationshipABSTRACT
A novel series of oxadiazole based amides have been shown to be potent DPP-4 inhibitors. The optimized compound 43 exhibited excellent selectivity over a variety of DPP-4 homologs.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Oxadiazoles/administration & dosage , Oxadiazoles/pharmacology , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacology , Administration, Oral , Animals , Binding Sites , Biological Availability , Dogs , Enzyme Activation/drug effects , Ether-A-Go-Go Potassium Channels/drug effects , Humans , Models, Molecular , Molecular Conformation , Oxadiazoles/chemistry , Protease Inhibitors/chemistry , Protein Conformation , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/metabolism , Hypoglycemic Agents/chemical synthesis , Phenylalanine/analogs & derivatives , Protease Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Calcium Channels, L-Type/drug effects , Cell Line , Crystallography, X-Ray , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Muscle Proteins/antagonists & inhibitors , Muscle, Skeletal/metabolism , NAV1.5 Voltage-Gated Sodium Channel , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rabbits , Sodium Channels , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. The optimized compound exhibited good pharmacokinetic profiles in three preclinical species.
Subject(s)
Adenosine Deaminase Inhibitors , Glycoproteins/antagonists & inhibitors , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacology , Pyridones/administration & dosage , Pyridones/pharmacology , Adenosine Deaminase/metabolism , Administration, Oral , Amides/chemistry , Animals , Biological Availability , Dipeptidyl Peptidase 4/metabolism , Dogs , Glycoproteins/metabolism , Humans , Inhibitory Concentration 50 , Macaca mulatta , Molecular Structure , Nitrogen/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Pyridones/chemistry , Pyridones/pharmacokinetics , Rats , Sensitivity and Specificity , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidases/antagonists & inhibitors , Dipeptidyl Peptidase 4 , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Hypoglycemic Agents , Protease Inhibitors/therapeutic use , Animals , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/physiology , Dogs , Female , Humans , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/toxicity , Isoleucine/analogs & derivatives , Isoleucine/chemistry , Isoleucine/therapeutic use , Isoleucine/toxicity , Isomerism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Protease Inhibitors/toxicity , Rats , Recombinant Proteins/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/therapeutic use , Thiazoles/toxicityABSTRACT
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. These are among the most potent compounds reported to date lacking an electrophilic trap. The most potent compound among these is 5-oxo-1,2,4-oxadiazole 44, which is a 3 nM DPP-IV inhibitor.
