Discovery and development of dipeptidyl peptidase-4 inhibitors

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blood glucose control regulation.[1]
Type 2 diabetes mellitus is a chronic metabolic disease that results from inability of the
hepatic glucose production can also play a role by increasing the body's demand for insulin. Current treatments, other than insulin supplementation, are sometimes not sufficient to achieve control and may cause undesirable side effects, such as weight gain and hypoglycemia. In recent years, new drugs have been developed, based on continuing research into the mechanism of insulin production and regulation of the metabolism of sugar in the body. The enzyme DPP-4 has been found to play a significant role.[2]

History

Since its discovery in 1967, serine protease DPP-4 has been a popular subject of research.

catalytic residue Ser630.[5]

In 1994, researchers from Zeria Pharmaceuticals unveiled cyanopyrrolidines with a

prolyl oligopeptidase (PEP) and also suffered from chemical instability. Ferring Pharmaceuticals filed for patent on two cyanopyrrolidine DPP-4 inhibitors, which they published in 1995. These compounds had excellent potency
and improved chemical stability.

In 1995, Edwin B. Villhauer at

DPP-4 inhibitor at the N-substituent.[3][6]

DPP-4 mechanism

glucagon-like peptide 1 (GLP-1) and glucose-dependent gastric inhibitory polypeptide (GIP) are released by the small intestine into the blood stream. These hormones regulate insulin secretion in a glucose-dependent manner. (GLP-1 has many roles in the human body. It stimulates insulin biosynthesis, inhibits glucagon secretion, slows gastric emptying, reduces appetite and stimulates regeneration of islet β-cells
.)

GLP-1 and GIP have extremely short plasma

half-lives due to very rapid inactivation, catalyzed by the enzyme DPP-4. Inhibition of DPP-4 slows their inactivation, thereby potentiating their action, leading to lower plasma glucose levels, hence its utility in the treatment of type 2 diabetes. (Figure 1).[2][7]

DPP-4 distribution and function

T-cell activating antigen
.)

DPP-4 selectively cleaves two

therapeutic strategy in the treatment of type 2 diabetes.[1][8]

DPP-4 characteristics

Since DPP-4 is a protease, it is not unexpected that inhibitors would likely have a peptide nature and this theme has carried through to contemporary research.[3]

Structure

DPP-4 inhibitors have been discovered and it is not that surprising considering the properties of the binding site:[9]

1. A deep

aromatic side chains
for achieving high affinity small molecule binding.

2. A significant

pharmacokinetic
behavior.

DPP-4 is a 766-amino acid

hydrophobic and is composed of the side chains: Tyr631, Val656, Trp662, Tyr666 and Val711. Existing X-ray structures show that there is not much difference in size and shape of the pocket that indicates that the S1-pocket has high specificity for proline residues[9][8]

Binding site

Fig.3: The key interactions between the ligand and DPP-4 complex. The ligand's basic amine forms a hydrogen bonding network. The nitrile reacts with the catalytic active serine and forms an imidate adduct

covalent bonds and slow, tight-binding kinetics but this group is also responsible for stability issues due to reactions with the free amino group of the P2-amino acid. Therefore, inhibitors without the electrophilic group have also been developed, but these molecules have shown toxicity due to affinity to other dipeptidyl peptidases, e.g. DPP-2, DPP-8 and DPP-9.[10]

DPP-4 inhibition and in fact, all compounds without the nitrile group in this research suffered a 20 to 50-fold loss of potency corresponding to the compounds containing the nitrile group.[11]

Discovery and development

It is important to find a fast and accurate system to discover new

aliphatic amines to identify fragments that could be placed in S1 and S2 sites of DPP-4
. On the other hand, these fragments were not very potent and therefore identified as a starting point to design better ones.
chemical feature responsible for inhibitory activity.[5]
The first DPP-4 inhibitors were reversible inhibitors and came with bad
substrate-like or non-substrate-like.[12]

Fig.4: A generic structure of a substrate-like inhibitor

Substrate-like inhibitors

Substrate-like inhibitors (Figure 4) are more common than the non-substrate-likes. They bind either

mimetic that occupies the S1-pocket. Large substituents on the 2-cyanopyrrolidine ring are normally not tolerated since the S1-pocket is quite small.[12]
Since
DPP-4 inhibitors to date, were discovered.[6]

Cyanopyrrolidines

Cyanopyrrolidines have two key interactions to the DPP-4 complex:[6]

1.

covalent bonds with the catalytically active serine
hydroxyl (Ser630), i.e. cyanopyrrolidines are competitive inhibitors with slow dissociation kinetics.

2. Hydrogen bonding network between the protonated amino group and a negatively charged region of the protein surface, Glu205, Glu206 and Tyr662. All cyanopyrrolidines have basic, primary or secondary amine, which makes this network possible but these compounds usually drop in potency if these amines are changed. Nonetheless, two patent applications unveil that the amino group can be changed, i.e. replaced by a hydrazine, but it is claimed that these compounds do not only act via DPP-4 inhibition but also prevent diabetic vascular complications by acting as a radical scavenger.

Structure-activity relationship (SAR)

Important

structure-activity relationship:[11]

1. Strict steric constraint exists around the

fluoro, acetylene, nitrile
, or methano substitution permitted.

2. Presence of a nitrile moiety on the pyrrolidine ring is critical to achieving potent activity

Also, systematic SAR investigation has shown that the ring size and

hydrophilic substitution can lead to excellent inhibitory activity.[6]

Chemical stability
Fig.5: Trans-rotamers are more stable then cis-rotamers. Cis-rotamers undergo intramolecular cyclization.

In general,

rotamer (Figure 5). Thus, preventing this conversion will increase stability. This prevention was successful when incorporating an amide group into a ring, creating a compound that kept the DPP-4 inhibitory activity that, did not undergo the intramolecular cyclization and was even more selective over different DPP enzymes. It has also been reported that a cyanoazetidine in the P1 position and a β-amino acid in the P2 position increased stability.[6]

Vildagliptin

pharmacodynamic effect.[6]

Saxagliptin
Fig.6: The basic structure of cyanopyrrolidines compared with vildagliptin, saxagliptin, and denagliptin

Researchers at

Bristol-Myers Squibb submitted a new drug application for Onglyza in the United States and a marketing authorization application in Europe.[13] Approval was granted in the United States by the FDA in July 2009 for Onglyza 5 mg and Onglyza 2.5 mg. This was later combined with extended-release metformin
(taken once daily) and approved by the FDA in January 2011 under the trade name Kombiglyze XR.

Denagliptin

Denagliptin (Figure 6) is an advanced

DPP-4 inhibitors.[14] GSK suspended Phase III clinical trials in October 2008.[15]

Azetidine based compounds

Informations for this group of inhibitors are quite restricted.

hydrophobic amino acid groups bound to the azetidine nitrogen and are active below 100nM.[16]

Non-substrate-like inhibitors

Non-substrate-like

aromatic ring that occupies the S1-pocket, instead of the proline mimetic.[12]

In 1999,

preclinical species. Optimization of these compounds finally led to the discovery of sitagliptin.[17]

Sitagliptin

Fig.7: The structure of sitagliptin

DPP-4 inhibitors with appended β-amino acid moiety. Further studies are being developed to optimize these compounds for the treatment of diabetes.[4]
In October 2006 sitagliptin became the first DPP-4 inhibitor that got FDA approval for the treatment of
bioavailable DPP-4 inhibitor was discovered by replacing the central cyclohexylamine in sitagliptin with 3-aminopiperidine. A 2-pyridyl substitution was the initial SAR breakthrough since that group plays a significant role in potency and selectivity for DPP-4.[2]

It has been shown with an X-ray crystallography how sitagliptin binds to the DPP-4 complex:[12]

1. The trifluorophenyl group occupies the S1-pocket

2. The trifluoromethyl group interacts with the side chains of residues Arg358 and Ser209.

3. The

amino group forms a salt bridge
with Tyr662 and the carboxylated groups of the two glutamate residues, Glu205 and Glu206.

4. The triazolopiperazine group collides with the phenyl group of residue Phe357

Fig.8: The structure of ABT-341

Constrained phenylethylamine compounds

Researchers at

Merck & Co
.

Pyrrolidine compounds

The

fluoro substituted pyrrolidines that show superior activity, as well as pyrrolidines with fused cyclopropylrings that are highly active.[20]

Xanthine-based compounds

This is a different class of inhibitors that was identified with HTS.

Boehringer-Ingelheim(BI) and Novo Nordisk.[21]
When
glucose tolerance.[22]

Alogliptin

Fig.9: Quinazolinone structure and alogliptin

U.S. Food and Drug Administration.[24]

Linagliptin

Fig.10: The structure of xanthine type inhibitors (TOP) and linagliptin (BOTTOM)

Researchers at BI discovered that using a buty-2-nyl group resulted in a potent candidate, called BI-1356 (Figure 10). In 2008 BI-1356 was undergoing phase III clinical trials; it was released as linagliptin in May 2011. X-ray crystallography has shown that that xanthine type binds the DPP-4 complex in a different way than other inhibitors:[12]

1. The amino group also interacts with the Glu205, Glu206 and Tyr662

2. The buty-2-nyl group occupies the S1-pocket

3. The uracil group undergoes a π-stacking interaction with the Tyr547 residue

4. The quinazoline group undergoes a π-stacking interaction with the Trp629 residue

Pharmacology

Comparative pharmacology of sitagliptin and vildagliptin.[18]
Drug Absorption Bioavailability (%) IC50 (nM) Mean volume of distribution (L) Protein binding (%) Half-life (hours,100 mg dose) Metabolism Excretion
Sitagliptin Rapidly absorbed with peak concentration at 1–4 hours 87 18 198 38 12.4 Small fraction undergoes hepatic metabolism via CYP 450 3A4 and 2C8 Excreted in an unchanged form in the urine (79%)
Vildagliptin Rapidly absorbed with peak concentration at 1–2 hours 85 3 70.5 9.3 1.68 (once a day) and 2.54 (twice a day) Hydrolysis resulting in a pharmacologically inactive metabolite. A fraction (22%) is also excreted unchanged by the kidneys Excretion of the metabolite is carried out through urine (85%) and feces (15%)

The

upper respiratory tract infections, sore throat and diarrhea.[5]

See also

References

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    PMID 17937986
  12. ^ a b c d e f g Pei, Zhonghua (March 2007), "From the bench to the bedside: Dipeptidyl peptidase IV inhibitors, a new class of oral antihyperglycemic agents", Current Opinion in Drug Discovery & Development, 11 (4): 515–532, archived from the original on 2012-10-17, Subscription required
  13. ^ AstraZeneca and Bristol-Myers Squibb submit New Drug Application in the United States and Marketing Authorization Application in Europe for ONGLYZA (saxagliptin) for the treatment of type 2 diabetes, archived from the original on 2011-07-07, retrieved 29 July 2013
  14. doi:10.1016/j.tet.2008.08.097
  15. ^ Denagliptin, archived from the original on 2013-11-30
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    doi:10.2337/diaclin.26.2.53
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  22. ^
    ProQuest 213848837 (registration required
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  23. PMID 17441705
    , retrieved 29 July 2013
  24. ^ FDA Continues Review of Takeda's New Drug Application for Alogliptin (SYR-322), a DPP- 4 agent for Type 2 Diabetes, retrieved 29 July 2013
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