Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents

Abstract

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, β-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC₅₀) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.

Keywords: DPP-4 inhibitors; SAR; bio-activity; heterocyclic scaffolds.

Figure 1

Work on DM during different timelines and demonstrating launch time of DPP-4 inhibitors.

Figure 2

DPP-4 protease (PDBID:1X70) activity inhibition using DPP-4 inhibitors which also induces various biological actions in peripheral tissues.

Figure 3

(A) DPP-4 enzyme sites (B) Structure of DPP-4 homodimer, the structure is prepared by using Pymol (C) illustrates subsites in the protein structure (PDBID:1X70) in CPK representation form.

Figure 4

Novel DPP-4 inhibitors under clinical trial pipeline.

Figure 5

Pleiotropic mechanism of DPP-4 inhibition.

Figure 6

Substrate and non-substrate based DPP-4 market approved inhibitors.

Figure 7

(A–H, I–L) General Scheme/Synthesis of market-approved DPP-4 inhibitor drug.

Figure 7

(A–H, I–L) General Scheme/Synthesis of market-approved DPP-4 inhibitor drug.

Figure 8

Structure of DPP-4 inhibitors: (A) omarigliptin and sitagliptin. (B) Compound (2) topmost potency against DPP-4 activity. (C) Compound (A–C) containing DPP-4 analogs. (D) Compound (3) containing DPP-4 design analogs [48,49,50].

Figure 9

Structure of DPP-4 inhibitors: (A) Compound (4) containing DPP-4 active subsites (PDBID:1X70) showing its β-propeller opening to the active site. (B) Compound (5).

Figure 10

Structure of DPP-4 inhibitors: (A) Halogen binding with Electrophiles and nucleophiles in various fashions. (B) In vitro potency of inhibiting DPP-4 on substituting R with halogen atoms (Compound 6). (C) SAR explains substituting R with halogen atoms (Compound 7). (D) Novel tricyclic moiety compound 8. (E) Compound (9) forming interaction with amino acid residues. (F) Design of Novel Hybrid synthesized DPP-4 inhibitor and their potent derivatives (Compound 10) [56].

Figure 11

Structure of DPP-4 inhibitors: (A) Structures of selected DPP-4 inhibitors. (B) Compounds (12) and (13). (C) Compound (14) and (15).

Figure 12

Structure of DPP-4 inhibitors: (A) Designing dual pharmacophore DPP-4 inhibitors. (B) Design of triazole-based uracil compound derivatives (Compound 16–20) and linagliptin and alogliptin.

Figure 13

Structure of DPP-4 inhibitors: (A) Potency of synthesized derivatives (21–24) against DPP-4 protease with IC₅₀. (B) SAR compact of benzoate and benzoic acid and its analogs-based DPP-4 inhibitor (25).

Figure 14

Structure of DPP-4 inhibitors: (A) SAR evaluation on basis of data of DPP-4 inhibition classification. (B) Scheme strategy for developing sulfonamide-quinoxaline based compounds.

Figure 15

Structure of DPP-4 inhibitors: (A) Different fragments used in developing sitagliptin. (B,C) Newly developed molecules consisting of N, O-disubstituted glycosamides 3, N, N-disubstituted glycinamides 4, and β-amino carbonyl 1,2,4-triazoles.

Figure 16

2D diagram of vildagliptin (PDBID:6B1E) and omariligliptin (PDBID:4PNZ).

Figure 17

Effect of compounds binding with S₂ extensive subsite illustrated by compound X and sitagliptin IC₅₀.

Figure 18

Synthesis of fluorophenyl-piperidine-based DPP-4 inhibitors.

Figure 19

Illustrating challenges during development of DPP-4 inhibitors.

Figure 20

Docked pose of Teneligliptin (PDBID:3VJK) (A) 3D interaction, (B) Surface view) and Anagliptin (PDBID:3WQH) (C) 3D interaction, (D) Surface view) showing various kinds of bond forming with amino acids in binding sites of DPP-4 with 3D interaction. Docked pose of Omarigliptin (PDBID:4PNZ) (E) 3D interaction, (F) Surface view) and sitagliptin (PDBID:1X70) (G) 3D interaction, (H) Surface view) showing various bond formation with amino acids in binding sites of DPP-4. Docked pose of Saxagliptin (PDBID:3BJM) [displayed in 3D interaction (I) 3D interaction, (J) Surface view)] and Linagliptin (PDBID: 2RGU) [displayed in (K) 3D interaction, (L)Surface view] compounds showing various bond formation with amino acids in binding sites of DPP-4 with 3-D interaction. Docked pose of Alogliptin ((M) 3D interaction, (N) Surface view) and Vildagliptin (PDBID:6B1E) ((O) 3D interaction, (P) Surface view) compounds showing various kinds of bond forming with amino acids in binding sites of DPP-4 with 3D interaction. Figure (G), alogliptin (PDBID:2ONC) highlights the H-bond formation of Glu205 and Glu206 residue with the 3-aminopyridine ring, Tyr547 forms H-bond with the benzonitrile ring of the compound, whereas Tyr666 was founded to be forming π-bond with the same ring (benzonitrile). In the graphical picture H, it is observed that all of the residues (Glu205, Glu206, and Tyr631) interact via H-bond with the compound (vildagliptin).

Figure 21

XP visualization pose of Sitagliptin showing hydrophobic enclosure (PDBID:1X70).