Review on Dipeptidyl Peptidase IV Inhibitors as a Newer Target for Diabetes Mellitus Treatment
Kavita Chandramore
Institute of Chemical Technology, Mumbai
*Corresponding Author E-mail: kavitachandramore@gmail.com
ABSTRACT:
Diabetes Mellitus (Type 2) is a major health issue all over the world. It is rapidly growing metabolic disorder characterized by hyperglycaemia with disturbances in carbohydrate, fat and protein metabolism. According to the International Diabetes Federation, more than 380 million people in the world suffer from Diabetes and this number will rise beyond 592 million in less than 25 years. The main classes of anti-diabetic drugs (biguanides, sulphonylureas, α-glucosidase inhibitors, thiazolidinediones, meglitinides) have side effects like weight gain and hypoglycaemia which makes them unsuitable for long term use. Thus newer anti-diabetic agents are still in need. Dipeptidyl Peptidase IV inhibitors have been found to be effective in the treatment of Type 2 Diabetes. DPP IV plays a major role in glucose metabolism. It is responsible for inactivation of incretins like GLP-1. Dipeptidyl Peptidase IV inhibitors increase insulin secretion by enhancing the level of incretin hormones. These incretin hormones are responsible for maintaining postprandial blood glucose levels by stimulating insulin secretion.
KEY WORDS: Diabetes Mellitus, Anti-diabetic, DPP IV, incretinharmone.
INTRODUCTION:
Diabetes is a chronic metabolic disorder characterized by hyperglycaemia with disturbances in carbohydrate, fat and protein metabolism. It occurs when the body either does not produce sufficient insulin (Type 1 Diabetes) or when it cannot effectively use the produced insulin (Type 2 Diabetes) which leads to increase plasma glucose levels.1 According to the International Diabetes Federation (IDF), more than 380 million people in the world suffer from Diabetes and this number will rise beyond 592 million in less than 25 years.
Also, About 80 percent of the affected people are from middle and low income countries. In 2011, about 62.4 million people in India suffered from diabetes as compared to 50.8 million in 2010. IDF predicts that about 100 million people in India would suffer from Diabetes by 20302 The number of people being diagnosed with Type 2 Diabetes is also increasing. People with diabetes are also at the risk of developing other complications including heart disease and stroke. The main classes of antidiabetic drugs either decrease hepatic glucose production (biguanides), stimulate insulin release from pancreatic β cells (sulfonylureas and glinides), reduce intestinal absorption of carbohydrates (α-glucosidase inhibitors) or improve insulins sensitivity in the peripheral tissues (thiazolidinediones and metformin).3 However, these have side effects like weight gain and hypoglycaemia which makes them unsuitable for long term use. Among the newer targets like sodium glucose co-transposter 2, 11β-hydroxysteroid dehydrogenase, glucagon receptor, DPP IV has been proved to be highly potential in treatment of diabetes.4 Two new classes of agents have recently been developed for the treatment of Type 2 diabetes based on incretin action: glucagons-like peptide-1 receptor agonists or incretinmimetics and dipeptidyl peptidase-IV (DPP-IV) inhibitors or incretin enhancers.
DIABETES MELLITUS:
World Health Organization (WHO) defines diabetes as a chronic disease where pancreas are unable to produce enough insulin or the body develops resistance to the use of insulin it produces. It is classified into insulin-dependent diabetes mellitus (IDDM), also known as type I and noninsulin-dependent diabetes mellitus (NIDDM), also known as type II. Type I diabetes mellitus is caused by an auto-immune reaction where the bodys defense system attacks the insulin-producing cells. Type II diabetes mellitus is characterized by insulin resistance and relative insulin deficiency. Other type of diabetes mellitusis the gestational diabetes mellitus, a condition that develops during the second trimester of pregnanc. Long term effects of diabetes include complications like heart disease, kidney damage, nerve damage, immune dysfunction etc.
Insulin:
Insulin is a peptide hormone produced by the beta cells of the pancreas and plays a major role in regulation of blood glucose. It consists of two peptide chains (A and B, of 21 and 30 amino acid residues, respectively). The synthesis and release of insulin depends on blood glucose concentration. Glucose enters the pancreatic beta cells via glucose transporter isoform (GLUT) 4 triggering an intracellular influx of calcium ions that promotes fusion of the insulin-containing secretory granules with the cell membrane, thereby promoting insulin secretion. Glucose-induced stimulation of insulin release from cells is biphasic. The initial rapid rise in insulin is followed by a more delayed and prolonged rise in insulin secretion. The overall role of insulin is to facilitate the uptake, storage and utilization of glucose, amino acids and fats.
Incretin effect:
The term incretin effect refers to stimulated insulin secretion after oral glucose ingestion compared to isoglycaemic parenteral or intravenous glucose administration. The two important incretin hormones are Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1).GIP is a 42-amino-acid peptide produced mainly by the K cells, located in the duodenum. GLP-1, on the other hand, is produced by the L cells, which are localized predominantly in the lower part of the small intestine.5These hormones are responsible for lowering postprandial blood glucose levels by exerting glucose-dependent insulin stimulatory actions. Both GIP and GLP-1 stimulate insulin secretion in a glucose-dependent manner, which is the main basis of the incretin effect. It has been estimated that the incretin hormones contribute by more than 70% to the insulin response to an oral glucose challenge.6 Besides the incretin action these hormones also contribute to decreased glucagon secretion, slowing gastric emptying and increase beta cell proliferation in islets of pancreas.7(Figure 1.1). However, these hormones are rapidly inactivated by the enzymeDipeptidyl Peptidase IV, leading to a half-life of GLP-1 less than 2 minutes and that of GIP ~7 minutes .
Figure1.1 :Functions of GLP 1
DIPEPTIDYL PEPTIDASE IV ENZYME:
DPP-IV is expressed as a 220 kDahomodimeric type IItransmembrane glycoprotein expressed on the surface of various cell types, including epithelial and endothelial cells, and lymphocytes. The enzyme was first described in 1967 and first crystal structure was obtained in 2003 (PDB ID 1N1M)8 DPP IV is a 766 amino acid transmembrane glycoprotein consisting of a cytoplasmic tail (residues 1-6), a transmembrane region (residues 7-28), and an extracellular part (29-766). The extracellular region consists of two domains: one catalytic domain (residues 508-766), having a catalytic triad Ser630-Asp708-His740 and α/β-hydrolase fold and other eight-bladed β- propeller chain (residues 56-497) (Figure 2.1). The catalytic site lies in a large cavity between the two extracellular domains and can be accessed through two active site openings. The enzyme is secreted as a monomer but forms a dimer for proteolytic activity.
Figure 2.1: Structure of DPP-IV enzyme
DPP-IV forms a homodimer (subunit A shown in green and subunit B in magenta). The inhibitor Val-Pyr is shown in CPK and colored by element: carbon (gray), nitrogen (blue) and oxygen (red). Five SS bridges (yellow). Carbohydrates (blue).
Mechanism of action of DPP-IV inhibitors:
DPP-IVenzyme selectively cleaves the N-terminal dipeptide from the penultimate position of GLP-1 and GIP thus makes them inactive (Fig 2.2). Competitive inhibition of the DPP-IV enzyme blocks the degradation of these incretin hormones and extend the duration of action of endogenous GLP-1, thereby stimulating insulin secretion, inhibiting glucagon release and slowing gastric emptying. The substrates for DPP-IV enzyme include incretin hormones like GLP-1 and GIP and a number of other bioactive peptides like neuropeptide Y, peptide YY, gastrin-releasing polypeptide, pituitary adenylate-cyclase-activating polypeptide, insulin-like growth factor-1, substance P.9
Figure2.2: Point of cleavage DPP-IV
Binding site of DPP IV:
DPP IVenzyme has two binding pockets(S1and S2). The S1 pocket consists of catalytic traid (Ser630, Asn710 and His740) and the S2 pocket involvs the key interaction with Glu205 and Glu206 dyad and Arg125 (Fig 2.3). In addition it has a large cavity surrounded by residue of Val207, Ser209, Arg358 and Phe357, which make S2 site more extensive. S1 and S2 pocket site is smaller in DPP-4 as compare to DPP-8 and 9.10
Figure2.3 :DPP-IV binding site
Marketed DPP IV inhibitors:
At present Eight competitive reversible inhibitors are in market with USFDA approvals in different years while many more are in different phases of clinical trials (Table 2.1). Saxagliptin, sitagliptin and linagliptin are licenced in most parts of the world; vildagliptin is licenced in Europe and Latin America and alogliptin is licensed in Japan and US.25 These all are more or less similar in their efficacy for inhibition of DPP IV in vitro according to one study where direct comparison was made under identical experimental conditions. The significant difference was observed in potency. IC50 values are 1 nM for linagliptin Vs. 19, 62, 50 and 24 nM, for sitagliptin, vildagliptin, saxagliptin and alogliptin, respectively. They all differ in structural chemistry, half life, metabolism, elimination and therefore in therapeutic dose and frequency.
Table 2.1: DPP IV inhibitors in the market
|
Generic Name (Brand Name) |
Drug |
Originator |
Year of Approval |
IC50nM |
|
Sitagliptin (Januvia) |
Merck & Co |
2006 |
18 |
|
|
Vildagliptin (Galvus ) |
Novartis |
2007 |
3.5
|
|
|
Saxagliptin (Onglyza) |
Bristol-Myers Squibb |
2009 |
3.37 |
|
|
Linagliptin (Tradjenta) |
BoehringerIngelheim |
2011 |
1 |
|
|
Alogliptin (Nesina) |
Takeda Pharmaceutical |
2013 |
7 |
|
|
Gemigliptin (Zemiglo) |
LG life sciences Ltd |
2012 |
16 |
Advantages and Disadvantages of DPP IV Inhibition Therapy
The main advantages of DPP IV inhibitors are oral bioavailability, sustainable reductions in HbAlc, low risk of hypoglycemia, weight neutrality and better glycaemic control over a longer duration of time. Disadvantages include lack of substrate specificity i.e. side effects due to the effect of DPP-IV on multiple substrates such as neuropeptides, cytokines, or chemokineslack of selectivity against other closely related enzymes.
Classification of DPP IV Inhibitors:
Based on their chemical structure DPP IV inhibitors can be broadly divided into:
A. Peptidomimetics i.e. those that mimic the penultimate dipeptide structure of DPP-IV substrates.
B. Non-peptidomimetics
Table 2.2:
Classification of DPP IV inhibitor
|
|
|
Peptidomimetic inhibitors
|
Glycine/Proline based inhibitors
|
· 2-Cyano pyrrolidine derivative · Fluoro olefin derivatives · Phosphonate derivatives · Pyrrolidine-based inhibitors without electrophilic group · Fluorinated pyrrolidine amides |
|
|
β alanine based inhibitors
|
· Triazolopiperazine derivatives · Piperazine-2-one derivatives · Thiazolidine and Thiazole derivatives · Imidazopiperidine derivatives · Pyrrolidin-2-yl-methyl amides/ sulphonamides and oxadiazole derivatives · 1,4-Diazepan-2-one derivatives |
|
Non-peptidomimetic inhibitors
|
|
· Xanthine Derivatives · Benzimidazole derivatives · Aminomethyl pyridine/pyrimidine derivatives · Aminobenzo[a]quinolizine derivatives · Quinazolinone and pyrimidinedione derivatives · Isoquinolone and Quinoline Derivatives · Indole derivatives |
Peptidomimetic inhibitors:
DPP-IV inhibitors which mimic the penultimate dipeptide bond of DPP IV substrate containing aproline mimic 5-membered heterocyclic rings like pyrrolidine, thiazolidine, cyanopyrrolidine or cyanothiazolidine are classified as peptidomimetics.
Glycine/Proline based inhibitors:
i) 2-Cyano pyrrolidine derivatives
These inhibitors contain a cyano functional group that binds with catalytic serine and forms an imidate. However they undergo intramolecular cyclization (Figure 2.4) of the free amino group at P2 site onto the electrophilic cyano or nitrile group at P1 site which leads to the stability issue. To enhance the potency and stability of this series of DPP IV inhibitors, various modifications have been done by different groups.
Figure2.4 :Intramolecular cyclization of the (S)-2-cyanopyrrolidine analogs
One of the approaches to overcome the stability issue was to increase the steric bulk on the amine group. A bulky adamantyl group was introduced which led to the discovery of Vildagliptin. Further various cyclopropanated derivatives were synthesized which gave yet another drug Saxagliptin.11. Another group synthesized bulky imidazolidine derivatives and found compound 4 to be most active (IC50: 2nM)12 and it also showed excellent selectivity over DPP 2, 8 and 9. Similarly another group synthesized cyclobutylatedproline derivatives (5) based on the hypothesis that cyclobutyl group would provide a stability enhancing effect and introduction of gem difluoro group would further enhance the stability by providing electronic repulsion to the incoming nitrogen nucleophile.13 Kato et al. evaluated the potency and selectivity of isoindoline class of DPP IV inhibitors. They found that compound 6 had excellent selectivity and potency (IC50: 3.4nm) for DPP IV as compared to other related peptidases. However the compounds showed high induction of CYP enzymes.14 Bioisosteric replacement of isoindoline, pyrazolopyrimidine was tried that imparted improved metabolic stability and safety and resulted in clinical candidate Anagliptin (Compund 7) (IC50: 3.8nM) which is approved for use in Japan.
Figure 2.5:Glycine/Proline based inhibitors
ii) Fluoro-olefin derivatives:
In an effort to mimic the peptide bond with a nonhydrolyzable peptide isostere, various compounds with fluoro-olefin were synthesized, but all of them showed activity in the low micromolar range which was assumed to be due to poorer hydrogen bonding abilityas compared to parent amide.15
iii) Phosphonate derivatives:
In the attempt to replace the nitrile with other electrophiles, various phosphonate derivatives were synthesized using diphenyl 1-(S)- prolylpyrrolidine-2(R,S)-phosphonate as a lead compound. All the compounds synthesized were irreversible inhibitors of DPP IV and also showed good selectivity against dipeptidyl peptidase II (DPP II). However the compounds showed inverse correlation between potency and stability.16
iv) Pyrrolidine-based inhibitors without electrophilic group:
A series of quinolineand isoquinoline derivatives were evaluated to explore the S2 extensive subsite of DPP IV. X ray co-crystalstructure of the most potent compound 10 (IC50: 0.37nM) showed that CH-π interactions between the quinolyl ring and the guanidinyl group of Arg358 enhances the activity and selectivity for DPP-4 inhibition.17 Further, linked bicyclic systems attached to the piperazine ring were investigated which led to the discovery of Teneligliptin (IC50: 0.37 nM) which has been approved for the treatment of type 2 diabetes in Japan.18
β-alanine based inhibitors or β-phenethylamine inhibitors:
The β- alanine based inhibitors were developed using HTS approach. The X ray crystallography studies of the screening hit 13, with DPP IV revealed that phenyl ring occupied in the hydrophobic proline pocket (S1).The protonated amino group formed hydrogen-bonding network to Glu205, Glu206 and Tyr662.
i) Triazolopiperazine derivatives:
Novel β-amino amide based DPP-IV inhibitors containing piperazine ring (compound 14) were reported, but these compounds showed poor pharmacokinetic properties.19 A variety of fused heterocycles were used in place of piperazine moiety to improve metabolic stability and pharmacokinetic properties, in addition to increasing DPP-IV inhibitory potency. Their efforts led to triazolopiperazine-based DPP-IV inhibitors and discovery of Sitagliptin (IC50: 18 nM).20
Figure 2.6:β-alanine based inhibitors
ii) 1,4-Diazepan-2-one derivatives:
Biftu et al synthesized DPP IV inhibitors by replacing triazolopiperazine ring ofsitagliptin by 1,4-diazepan-2-one. Compound 16 was found highly potent (DPP-4 IC50: 2.6 nM), >25,000 fold selective against DPP-2 and 8.21
iii) Piperazine-2-one derivatives:
Kim et al synthesized a series of β-amino amide containing substituted piperazine-2-one derivatives as DPP IVinhibitors for the treatment of type 2 diabetes. They found that Compound 17 (Evogliptin, DA-1229), showed potent DPP-4 inhibition pattern in several animal models (IC50: 1nM). Currently the compound is in phase II clinical trials.22
Non peptidomimetic inhibitors:
i) Xanthine Derivatives:
High-throughput screening of compounds undertaken by Eckhardt et al. gave compound 18 which showed low micromolar activity. Various substituents on the xanthine core of compound 18 were done and evaluated especially on the residues at N-1, N-7, and C-8 because of their higher impact on activity. This led to the discovery of a highly potent, selective and long acting
druglinagliptin (DPP-4 IC50: 1.0 nM,10,000-fold selectivity over both DPP-8/9).23
Figure 2.7:Non peptidomimetic inhibitors
ii) Benzimidazole derivatives:
Wallace et al. utilized structure-based design starting with an initial hit Compound 20 (IC50: 30 μM), 2-phenylbenzylamine to build a novel series of non-covalent benzimidazole based DPP IV inhibitors. The representative compound 21 was found to be potent (DPP-4 IC50: 8 nM) and selective (DPP-8 IC50>100 μM).24
iii) Aminomethyl pyridine/pyrimidine derivatives:
Variousaminomethyl pyridines were synthesized based on the anticipation that presence and the position of the primary amine and the amide groups on the pyridine ring might be critical for the inhibitory activity. Compound 22 showed high potency and excellent DPP-4 selectivity (IC50:10nM (DPP-4) and 6600 nM (DPP-8)) and no toxicity in mammalian cell culture.25
iv) Aminobenzo[a]quinolizine derivatives:
2-Aminobenzo[a]quinolizine 23 (IC50: 520 nM) was identified as submicromolar HTS hit by Hoffmann-La Roche Ltd (Lόbbers et al., 2007). Modifications to compound 23 led to discovery of compound 24 carmegliptin(IC50: 6.8 nM).26
v) Quinazolinone and pyrimidinedione derivatives:
Various quinazolinone derivatives were syntheiszed and compound 25 was found to be active (IC50: 10nM) but suffered from short metabolic half-life due to oxidation at 6 or 7 position of phenyl ring. The quinazoline ring was replaced with other heterocycles to improve the metabolic stability. Replacing the quinazolinone with a pyrimidinedione resulted in compound 26 Alogliptin.
vi) Isoquinoloneand Quinoline Derivatives:
HTS of in-house chemical library by Banno et al led to the identification of an isoquinolone-based hit compound 27 (IC50: 16 μM) and optimization gave compound 28 (IC50: 240 nM).27 (Banno et al., 2011). Scaffold hopping strategy led to identification of compound 29 which showed DPP-4 IC50 value of 1.3 nM with very high selectivity against DPP-2 (IC50: 20 μM) and DPP- 8/9 (IC50> 60 μM).28
vii) Indole derivatives:
Using Denovo design, a series of potent and selective DPP IV inhibitors containing indole scaffold was synthesized by Xiao et al, and compound 30 was found to be highly potent and selective (IC50: 232 nM).29
2.7 Binding interactions with DPP IV enzyme:
Based on the study of both Peptidomimetic and non- peptidomimetic DPP IV inhibiotrs, it can be concluded that the minimum requirement for a compound to show DPP IV inhibitory activity is interaction with the Glu205 and Glu206 dyad in S2 pocket and occupation of hydrophobic S1 pocket. In case of peptidomimetics containing electrophilic group, the electrophile interacts via covalent bonding with Ser630. Additional interactions known to achieve nanomolar affinity include phenyl rings of Phe357 and Tyr547 which interact with different aromatic ligand fragments. The non-peptidomimetics have been designed to explore the S2 extensive subsite to allow additional interactions. Also, as interaction with subsites increases, DPP-IV inhibition increases.
CONCLUSIONS:
The DPP-4 inhibitors are the first new therapeutic class of oral antihypergl ycaemic drug for T2DM for many years. The understanding that DPP-IVis the major inactivator of GLP-1 prompted the clinical development and application of DPP-IVinhibitors for the treatment of Type 2 diabetes to improve glycaemic control by increasing GLP-1 longevity. Clinical trials indicate that the selective DPP-IV inhibitors alogliptin, saxagliptin, sitagliptin and vildagliptin are generally well tolerated, with the benefits of increases in active incretin hormones, less circulating glucagon and the possibility of preserved or enhanced β-cell function. As the DPP-IVfamily areubiquitous serine proteases with numerous functions, the roles of DPP-IV as well as its inhibitory effects continue to be studied extensively. Although DPP -IV and the related enzymes DPP-8 and DPP-9 form a family of prolinetargetedserine proteases and have a close structural similarity, they also have a number of dissimilarities. One notable dissimilarityis that DPP-IV is extracellular, whereas DPP-8 and DPP-9 are present exclusively in the cytoplasm.
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Received on 30.05.2017 Accepted on 20.06.2017
© Asian Pharma Press All Right Reserved
Asian J. Pharm. Res. 2017; 7(4): 230-238.
DOI: 10.5958/2231-5691.2017.00036.3