vildagliptin and Diabetes-Mellitus--Type-2

Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Structure-Activity Relationship

The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Structure-Activity Relationship

Emerging as an epidemic of the 21st century type 2 diabetes has become a major health problem throughout the globe. The number of deaths attributable to diabetes reflects the insufficient glycemic control achieved with the treatments used in recent past. DPP-4 inhibitors have been investigated as a new therapy with novel mechanisms of action and improved tolerability. DPP-4, a protease that specifically cleaves dipeptides from proteins and oligopeptides after a penultimate N-terminal proline or alanine, is involved in the degradation of a number of neuropeptides, peptide hormones and cytokines, including the incretins GLP-1 and GIP. As soon as released from the gut in response to food intake, GLP-1 and GIP exert a potent glucose-dependent insulinotropic action, thereby playing a key role in the maintenance of post-meal glycemic control. Consequently, inhibiting DPP-4 prolongs the action of GLP-1 and GIP, which in turn improves glucose homeostasis with a low risk of hypoglycemia and potential for disease modification. Indeed, clinical trials involving diabetic patients have shown improved glucose control by administering DPP-4 inhibitors, thus demonstrating the benefit of this promising new class of antidiabetics. Intense research activities in this area have resulted in the launch of sitagliptin and vildagliptin (in Europe only) and the advancement of a few others into preregistration/phase 3, for example, saxagliptin, alogliptin and ABT-279. Achieving desired selectivity for DPP-4 over other related peptidases such as DPP-8 and DPP-9 (inhibition of which was linked to toxicity in animal studies) and long-acting potential for maximal efficacy (particularly in more severe diabetic patients) were the major challenges. Whether these goals are achieved with the present series of inhibitors in the advanced stages of clinical development is yet to be confirmed. Nevertheless, treatment of this metabolic disorder especially in the early stages of the disease via DPP-4 inhibition has been recognized as a validated principle and a large number of inhibitors are presently in various stage of pre-clinical/clinical development. Sitagliptin is a new weapon in the arsenal of oral antihyperglycemic agents. This review will focus on the journey of drug discovery of DPP-4 inhibitors for oral delivery covering a brief scientific background and medicinal chemistry approaches along with the status of advanced clinical candidates.

Topics: Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glutaminase; Humans; Hypoglycemic Agents; Insulin; Intracellular Signaling Peptides and Proteins

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Drug Evaluation, Preclinical; Humans; Protease Inhibitors; Structure-Activity Relationship

Topics: alpha-Glucosidases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Indoles; Models, Molecular; Molecular Structure; Structure-Activity Relationship

Our previously reported carboxyl-containing DPP-4 inhibitors were highly potent but were poorly bioavailable. Esters of the carboxyl analogs exhibited a significant DPP-4 potency loss albeit with enhanced oral absorption. Herein, we described identification and structure-activity relationship (SAR) exploration of a novel series of benzoic acid and ester derivatives as low single-digit nanomolar DPP-4 inhibitors. Importantly, the esters displayed comparable activities to the acids counterparts. Molecular simulation revealed that ester adopts a similar binding mode to acid. Moreover, the selected esters and acids demonstrated high selectivity and low cytotoxicity, as well as good metabolic stability. And more importantly, the esters possessed excellent pharmacokinetic profiles for oral administration. The best compound ester 19b demonstrated long DPP-4 inhibition in vivo, and robustly improved the glucose tolerance in normal and db/db mice while ensuring glucose-lowering potency in chronic treatment. Our results supported that the compound 19b can be served as a potential candidate for the treatment of type 2 diabetes.

Topics: Administration, Oral; Animals; Benzoic Acid; Cell Line; Cell Survival; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Esters; Humans; Hypoglycemic Agents; Injections, Intravenous; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Uracil

Topics: Animals; Benzoic Acid; Cell Survival; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Prodrugs; Structure-Activity Relationship; Xanthine

In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27-15.78 µM). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.

Topics: Alkaloids; Animals; Azocines; Binding Sites; Camphor; Catalytic Domain; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Male; Mice; Molecular Docking Simulation; Pyrrolidines; Quinolizines; Structure-Activity Relationship

A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).

Topics: Animals; Cell Line; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Mice; Mice, Inbred ICR; Models, Molecular; Nitriles; Pyrroles; Structure-Activity Relationship

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified 26 as an early lead. Compound 26 demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats.

Topics: Allosteric Regulation; Aminopyridines; Animals; Diabetes Mellitus, Type 2; Enzyme Activators; Glucokinase; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Mice; Mice, Inbred C57BL; Rats; Rats, Zucker; Structure-Activity Relationship; Thiazoles; Young Adult

A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC(50)=0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP-4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague-Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Tolerance Test; Hypoglycemic Agents; Male; Mice; Mice, Inbred ICR; Nitriles; Pyrrolidines; Rats; Rats, Sprague-Dawley

In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Imidazoles; Molecular Docking Simulation; Quinolines

A series of novel azobicyclo[3.3.0]octane derivatives were synthesized and evaluated as dipeptidyl peptidase 4 (DPP-4) inhibitors. The effort resulted in the discovery of inhibitor 2a, which exhibited excellent efficacies in an oral glucose tolerance test. Introduction of methyl group (2j) could prolong the inhibition of serum DPP-4 activity.

Topics: Animals; Azo Compounds; Bridged Bicyclo Compounds; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Tolerance Test; Hypoglycemic Agents; Mice; Mice, Inbred ICR; Octanes; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

A series of novel bicyclo[3.3.0]octane derivatives have been synthesized and found to be dipeptidyl peptidase 4 (DPP-4) inhibitors. Compounds 10a and 10b demonstrate good efficacies in oral glucose tolerance tests.

Topics: Animals; Bridged Bicyclo Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Glucose Tolerance Test; Mice; Mice, Inbred Strains; Octanes

Dipeptidyl peptidase IV (DPP IV) is a key regulator of insulin-stimulating hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus it is a promising target for the treatment of Type 2 Diabetes mellitus (T2DM). Inhibition of plasma DPP IV enzyme leads to enhanced endogenous GLP-1 and GIP activity, which ultimately results in the potentiation of insulin secretion by pancreatic beta-cells and subsequent lowering of blood glucose levels, HbA[1(c)], glucagon secretion and liver glucose production. Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. These drugs have been approved as a once-daily oral monotherapy or as a combination therapy with current anti-diabetic agents like pioglitazone, glibenclamide, metformin etc. for the treatment of T2DM. Several other novel DPP IV inhibitors are in pipeline. The present review summarizes the latest preclinical and clinical trial data of different DPP IV inhibitors with a special emphasis on their DPP8/9 fold selectivity and therapeutic advantages over GLP-1 based approach.

Topics: Adamantane; Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drugs, Investigational; Humans; Hypoglycemic Agents; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Substrate Specificity; Treatment Outcome; Triazoles; Vildagliptin

The induction of conformationally restricted N-(aryl or heteroaryl)-3-azabicyclo[3.1.0]hexane derivatives at P(2) region of compounds of 2-cyanopyrrolidine class was explored to develop novel DPP-IV inhibitors. The synthesis, structure-activity relationship, and selectivity against related proteases are delineated.

Topics: Amino Acid Motifs; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Hexanes; Humans; Ligands; Models, Chemical; Molecular Conformation; Piperidines; Protease Inhibitors; Structure-Activity Relationship; T-Lymphocytes

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Administration, Oral; Animals; Binding Sites; Caco-2 Cells; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Female; Glucose Intolerance; Glycoproteins; Humans; Hypoglycemic Agents; Macaca fascicularis; Models, Molecular; Molecular Structure; Pyridines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Rats, Zucker; Stereoisomerism; Structure-Activity Relationship