Alogliptin, a pyrimidinedione
based potent and selective DPP 4 inhibitor was discovered by Syrrx (Takeda) in
order to treat patients suffering from type 2 diabetes. There were a lot of
problems faced prior to the development and discovery of Alogliptin. One of the
main problems was to identify a suitable heterocyclic scaffold that could be
used clinically. Alogliptin discovery begun from a xanthine derivative which
This was chosen from 80 co-crystal structures which had been collected from
high throughput crystallography. (Zhang et al., 2011)

The 2-chlorobenzyl group had
been substituted by a 2-cyanobenzyl moiety, this caused a polar interaction
between the cyano group and Arg125. Furthermore the piperazinyl group had been
substituted by a 3-aminopiperidine moiety, this caused in increase in potency. A
selective and potent inhibitor was provided by substitution of the central ring
by a quinazolinone scaffold which lead to inhibition of CP450 and hERG
blockade. In order to conquer these problems further SAR studies were conducted.
Alogliptin was produced from substitution of the quinazoline ring by a
pyrimidinone moiety which changed to a pyrimidinedione ring. Another problem
faced was to discover the favoured stereochemistry at the C-3 position of the
aminopiperidine moiety. Prior to this the favoured R-stereochemistry was discovered
by preparation of both of the enantiomers of the xanthine-based inhibitor and testing
them for their in vitro inhibitory properties. Another issue which needed to be
solved was the favoured orientation of the 3-amino group. The 3 amino group
favoured an axial orientation on the piperidine ring which was discovered by
the co-complex of Alogliptin with the active site of DPP IV. Calculations such
as the ab initio which took place on the axial and equatorial conformation
indicated a major stabilization of the axial conformation. This was as a result
of the nitrile amine interaction. A chair form was displayed in the axial
conformer and a boat form was noted in the equatorial conformer of the piperidine
ring. In conclusion task of the axial chair conformer aided by numerous
calculations had met the desired fit to the binding site. Once this was done and
toxicology assessments had been conducted to assess the in vivo profile of
Alogliptin in rats and dogs, Alogliptin had been considered for development
clinically. (Parsa and Pal, 2011)

Teneligliptin was discovered
through a series of processes. (Yoshida et al., 2012) Firstly investigations
took place on the connections between bicyclic heteroarylpiperazines replaced
at the ?-position of the proline structure while investigating
l-prolylthiazolidines. As a result of this a very potent, selective, long
lasting and orally active DPP-4 inhibitor was discovered known as 3-(2S,4S)-4-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-ylpyrrolidin-2-ylcarbonylthiazolidine
(8 g). This has a distinctive structure consisting of 5 consecutive rings. DPP
4 potency had been increased as well as selectivity. This was found by an x-ray
co-crystal structure of 8 g in DPP-4 showing the prime interaction amongst the
phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4. The
compound 8g, at 0.03mg/kg or even at a higher dose showed notable inhibitory
effects on the increase of plasma glucose levels following an oral glucose load
in Zucker fatty rats. The compound 8g now known as Teneligliptin has been
approved in treating type 2 diabetes in Japanese patients. (Singh, 2017)

Structural based
drug design was used in order to aid the discovery process of trelagliptin. Co –
complex x ray crystal structures were acquired which showed Trelagliptin binding to DPP 4. Fig 1 displays the co-complex
structures of trelagliptin in the active site of DPP-4.

Observations of this led to the
fact that the aminopiperidine creates a salt bridge to Glu205/206. On the other
hand the cyanobenzyl group occupies the S1 pocket and upon doing so it has an interaction
with Arg125. A key hydrogen bond is formed as a result of 2-position carbonyl
interacting with the backbone NH of Tyr631. Furthermore the uracil ring pi
stacks with Tyr547. One of the key features of the atomic structure of
trelagliptin is that there is a fluorine atom at the 5-position of the
cyanobenzyl group. By looking at the area near the fluorine atom one can note
that the DPP 4 active site shows the proximity of the following residues Trp659,
Tyr631, and Val656. Fig 2

After observing the radius of the
elements it was found that Van der Waals distance of the fluorine dictated that
hydrogen atoms are the only residues that fit this category. A permanent
partial positive charge is held by the hydrogen atoms this is because of the
position the aromatic rings of Trp659 and Tyr631 take. Furthermore another positive
charge is present which is inducible and occurs on the side chain of Val656.

In comparison to hydrogen atoms
at the 5-position, fluorine contains a persistent partial negative change
therefore they would be able to produce an added attractive force between
ligands and proteins.

Although the added attraction
would be relatively low in terms of its effectiveness it might still be accountable
for the 4-fold potency rise in trelagliptin. Trelagliptin binds to DPP-4
non-covalently and does not cause toxicity.  (Grimshaw et al., 2016)


Dipeptidyl peptidase-4 (DPP – 4) inhibitors are a class of
oral hypoglycaemic drugs, used in the treatment of type 2 diabetes mellitus.

They aim to inhibit the action of an enzyme known as DPP – 4
which destroys the hormone incretin.

Incretins aid the body by producing an increased amount of
insulin when required, additionally incretin reduces glucose levels when
glucose is not needed. The incretin hormone is released during the day and the
amount of incretin released is higher during meals.

DPP – 4 inhibitors exert their therapeutic effects by
increasing incretin which inhibits the release of glucagon. This causes an
increase in insulin secretion leading to a decrease of gastric emptying and a
reduction of blood glucose levels.

As a result of this DPP 4 inhibitors make it easier to
control glycaemia increasing active incretin levels.

A physiological mechanism is used by DPP 4 inhibitors in
order to control hyperglycaemia.

The mechanism works by stimulation of the secretion of
insulin from B – cells. This leads to a decrease in secretion of glucagon from
pancreatic A – cells which causes a reduction in the build up of glucose by the
liver. DPP 4 inhibitors are also known to improve liver dysfunction in those
whom suffer from type 2 diabetes.

The level of efficacy is high in DPP 4 inhibitors in terms
of keeping levels of glycosylated haemoglobin at a low constant. Studies
conducted in vitro and on animals have shown that DPP 4 inhibitors can block
apoptosis of B – cells which can be beneficial for their regeneration and

The benefits of taking DPP 4 inhibitors rather than some
other anti-diabetic agents is that DPP 4 inhibitors do not affect the body
weight and have a low risk of hypoglycaemia.

The first DPP 4 inhibitor Sitagliptin was FDA approved in
the year of 2006

A recently approved DPP 4 inhibitor Omarigliptin was
approved in Japan in the year 2015.  A
study was conducted in order to assess the safety and efficacy of omarigliptin
in comparison to Sitagliptin.

The sample tested upon were Japanese patients of whom
suffered from type 2 diabetes. Randomized control trials was the method used
for this study which took place over a time period of 24 weeks. The sample size
consisted of 414 patients whom were split into groups either taking omarigliptin
25mg once weekly, Sitagliptin 50mg once daily or a placebo. One of the
hypotheses tested was that omarigliptin is non inferior to Sitagliptin in
reducing HbA1c levels. Results were in correlation to this hypothesis, this was
as the results showed that the least squares mean difference in the baseline
changes of HbA1c of omarigliptin and Sitagliptin was only -0.02%. Due to their
being such a small difference this met the criteria for omarigliptin not being
inferior to Sitagliptin. Also to note over the 24 week period of time there
wasn’t any clinically important differences in the incidence rates of the drugs
amongst the patients. However there was 1 incident were symptomatic
hypoglycaemia occurred in the Sitagliptin group, one the other hand no incidents
occurred in the omarigliptin group. Moreover body weight had not been effected
as a result of taking omarigliptin. 
There isn’t any major difference between the DPP 4 inhibitors
Sitagliptin and Omarigliptin in terms of their therapeutic effects.   

DPP 4 inhibitors such as Vildagliptin, Sitagliptin and
Saxagliptin are efficient when taken on their own and can be taken alongside
other oral anti diabetic drug such as metformin and acarbose

A pooled analysis study consisting of 25 randomised clinical
trials was conducted which showed that Sitagliptin does not lead to any
cardiovascular risks in sufferers of type 2 diabetes.

A clinical trial was conducted to assess the efficacy and
safety of omarigliptin.

Patients whom suffer from type 2 diabetes who currently use
metformin and glimepiride were tested on with omarigliptin. Tests took place
for 24 weeks and findings showed that taking omarigliptin once weekly improved
glycaemic control and was tolerated well. Furthermore omarigliptin was found to
be better than the former drugs used which were metformin and glimepiride.
Omarigliptin was taken once weekly amongst 4202 patients of type 2 diabetes in
order to assess whether or not there were any cardiovascular side effects
associated with consuming this drug. After 96 weeks results indicated that the
drug omarigliptin was well tolerated amongst consumers and it did not increase
the risks of cardiovascular problems such as heart failure.

A meta-analysis was conducted to investigate the relationship
between DPP 4 inhibitors and risks associated with them causing heart failure
in patients with type 2 diabetes. The methods used were randomized control
trials. Findings showed that the risks of heart failure upon dosing with
Vildagliptin, Sitagliptin or Saxagliptin were low. However there was a
relatively high risk of heart failure with Alogliptin. The order of safest to
least safe in terms of causing heart failure was from Vildagliptin,
Saxagliptin, Sitagliptin, Linagliptin and Alogliptin

A major difference between Linagliptin and other DPP 4
inhibitors is that Linagliptin has a largely non renal excretion route
therefore adjustment of dose is not required when given to patients suffering
from renal impairment. Furthermore dose adjustments are also not required for
patients suffering from hepatic impairment. This could be due to Linagliptin
possessing a large therapeutic window. In DPP 4 inhibitors Sitagliptin,
Saxagliptin and Alogliptin dose adjustment would have to be required for
patients suffering from renal impairment

Warning labels were added to the DPP 4 inhibitors
sitagliptin, saxagliptin, linagliptin and alogliptin as they have the potential
to cause severe joint pain that may be disabling.

A meta-analysis conducted by scientists Marfella, Barbieri,
Grella, Rizzo, Nicoletti and Paolisso to compare the effects of DPP-4
inhibitors, Sitagliptin and Vildagliptin had been executed

Findings from this study had shown that there had been
similar reductions in HbA1c of both drugs. Although evidence showed that
Vildagliptin had decreased the glycaemic changes at a greater magnitude than
that of Sitagliptin.

The development process of DPP – 4 inhibitors started when
DPP-4 inhibitors were used as a therapeutic agent for the treatment of type 2

This was based upon the fact that DPP-4 is the primary
enzyme used in the regulation of the incretin hormone GLP-1 which is used for
treatment of type 2 diabetes. 

From these findings a hypothesis was made that inhibition of
DPP-4 could cause increased GLP-1 circulation

This hypothesis was confirmed by research scientists Balkan,
Kwasnik, Miserendino, Holst and Li whom used Zucker fatty rats for testing
DPP-4 inhibitors on and had found that glucose tolerance and insulin secretion
had improved as a result of this.

This was caused by an increase in GLP-1 which occurred due
to DPP-4 inhibitors.

GLP-1 stimulates release of insulin and causes inhibition of
glucagon production in a way which relies upon glucose therefore the mechanism
is believed to have a low risk of hypoglycaemia.

In the year of 2002 a 4 week study had been conducted in
order to learn about the inhibitory effects of Dipeptidyl Peptidase IV on
metabolic control in type 2 diabetes. Findings had shown that HbA1c had reduced
by 0.6% in patients after being treat with DPP 4 inhibitors

This study did not discover the underlying mechanisms
responsible for the beneficiary effects of DPP -4 inhibitors on the glycaemic
control in humans however.

A systematic review and meta-analysis study was conducted by
Ling Li and colleagues

The aim of this review was to investigate the possibility of
DPP-4 inhibitors causing heart failure in patients suffering from type 2
diabetes. Findings from this study showed that risks of DPP 4 inhibitors
causing heart failure in patients suffering from type 2 diabetes is unknown.
This is due to a lack of relevant evidence in support of either DPP 4
inhibitors causing heart failure or not. However evidence was found which
indicated that DPP 4 inhibitors may have detrimental effects on those already
suffering from cardiovascular diseases.

Specifically the drugs which were responsible for slight
increased risks of heart failure were Saxagliptin and Alogliptin, this lead to
the FDA to attach warning labels on these drug packages.

The drug Saxagliptin was tentatively approved which means
that even though the drug meets the safety, efficacy and manufacturing
standards it still cannot be sold in the US.

Saxagliptin has also been rejected in India due to patenting

Comparisons between different DPP 4 inhibitors on their
therapeutic effects, metabolic properties and dosage differences are scarce.
Current data used in order to compare and contrast the properties of DPP 4
inhibitors shows that almost all obtainable DPP 4 inhibitors have similar
effects and efficacy.

Teneligliptin, a DPP 4 inhibitor approved in Japan in the year
2012 hasn’t been in the market for long enough therefore post marketing
surveillance is still ongoing. In order to draw a comparison between
teneligliptin and other DPP 4 inhibitors additional time would be required to
see whether any new discoveries on the drug are found.

In the year of 1993 in vitro studies were performed, these
studies found that DPP 4 causes both gip and glp – 1 to become n-terminally
degraded to an inactive metabolite. In the year of 1995 DPP 4 inhibition begun
to be something which was considered in order to treat sufferers of type 2
diabetes. In 2001 a study was conducted on type 2 diabetes patients, from this
study clinical evidence showed glucose to become decreased along with fasting
blood glucose and HbA1c after consumption of an early DPP 4 inhibitor by the
pharmaceutical company Novartis. This provoked further research which led to
testing Vildagliptin for 52 weeks.

GLP 1 levels are increased as a result of DPP 4 inhibition
which causes a prevention and inactivation of GLP 1. Increase in GLP 1 is
present within 24 hours of consumption. 

Studies conducted on animals show that DPP 4 inhibition does
not improve glucose homeostasis.

Rather GLP 1 stimulates insulin secretion which causes an
improvement in the acute B cell function by inhibition of DPP 4. Reports for
Vildagliptin have supported this.

Inhibition of glucagon secretion
by DPP 4 inhibition is also an important mechanism in improvement of glycaemic
control. This has been shown when Vildagliptin at 100mg was consumed for 4

Furthermore, a study showed that
the glucagon profile for a whole 24-hour period is reduced by Vildagliptin.

A recent study found that by
reducing glucagon levels due to an increase of insulin secretion by consumption
of 100mg Vildagliptin on patients with type 2 diabetes, had caused an
inhibition of hepatic glucose production.  

DPP 4 inhibitions might also
improve insulin sensitivity, findings have supported this as treatment with
Vildagliptin using both direct and indirect measure insulin sensitivity along
with a hyperinsulinemia euglycemic clamp test.

This could be due to a reduction
of levels of glucagon as a result of DPP 4 inhibition that causes an
improvement of insulin action by improved metabolic control.

A DPP 4 inhibitor program at Merck was provoked in the year
1999 due to the emergence of glucagon-like peptide 1 (GLP-1) as a valid advance
in treating patients suffering from diabetes. The programme started with the
licensing of DPP-4 inhibitors threo- and
allo-isoleucyl thiazolidide, although problems faced with these chemicals lead
to their development to become discontinued.

The problems associated with
both of these DPP 4 inhibitors were that they produced toxicity which was
confirmed by studies conducted on rats and dogs. An observation was made as
both of the compounds inhibited the proline peptidases DPP8 and DPP9 this led
to the hypothesis that inhibition of DPP8 and/or DPP9 could cause toxic

This lead to attempts based on
discovering a selective DPP 4 inhibitor. Work begun on isoleucyl thiazolidide
which was later discontinued as the chemical compound lacked selectivity.
Structural studies took place on two screening leads which led to the discovery
of a very selective B- amino acid piperazine.

In order to keep the piperazine
moiety balanced, a number of bicyclic derivatives were arranged, extensive
metabolization occurred in vivo. This was done until a potent and selective
triazolopiperazine series could be discovered. These anologs presented great
pharmacokinetic effects in the preclinical species

The discovery of Sitagliptin which
is a very selective DPP 4 inhibitor was made due to the optimization of these
series of clinical trials.



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