this seminar talk aboute all the steps of PPIs developement.

1. Done By: Ali H. Abbas
Msc Student
Pharmaceutical Chemistry Department
PROTON PUMP INHIBITORS
DISCOVERY AND
DEVELOPMENT

2. HISTORY OF DISCOVERY:
Evidence emerged by the end of the 1970s that the newly
discovered proton pump (H+,K+-ATPase) in the secretory
membrane of the parietal cell was the final step in acid
secretion. Literature from anaesthetic screenings led
attention to the potential antiviral compound
pyridylthioacetamide which after further examination
pointed the focus on an anti-secretory compound with
unknown mechanisms of action called timoprazole.
Timoprazole is apyridylmethylsulfinyl benzimidazole and
appealed due to its simple chemical structure and its
surprisingly high level of anti-secretory activity.

3. BASIC STRUCTURE:
PPIs can be split into two groups based on their
basic structure. Though all have
a substituted pyridine part,
 first group has linked to various
benzimidazoles.
Second group has linked to a substituted
imidazopyridine.

4. TEMOPRAZOLE:
In the year 1975, timoprazole was found to inhibit acid
secretion irrespective of stimulus, extracellular or
intracellular.Studies on timoprazole revealed enlargement
of the thyroid gland due to inhibition of iodine uptake as
well as atrophy of the thymus gland. A literature search
showed that some substituted mercapto-benzimidazoles
had no effect on iodine uptake and introduction of such
substituents into timoprazole resulted in an elimination of
the toxic effects, without reducing the antisecretory
effect.

6. The first step shows protonation of the pyridine
ring and the benzimidazole ring inside theparietal
cell. The protonated molecule cannot leave the
cell any more. The last group of steps shows the
active forms, a permanent tetracyclic sulfenic acid
along with its dehydrated form of a sulfenamide,
and how either of those can form disulfides with
one or more H+/K+-ATPase cysteins accessible from
the luminal surface of the enzyme.

7. OMEPRAZOLE:
A derivative of timoprazole, omeprazole, was
discovered in 1979, and was the first of a new class
of drug that control acid secretion in the stomach, a
proton pump inhibitor (PPI). Addition of 5-methoxy-
substitution to the benzimidazole moiety of
omeprazole was also made and gave the compound
much more stability at neutral pH.

8. Omeprazole was the first PPI on the market, in
1988. It is a 1:1 racemate drug with a backbone
structure of timoprazole, but substituted with
two methoxy and two methyl groups:
 the methoxy group one at position 6 of the
benzimidazole and the other at position 4 of
the pyridine.
 the methyl groups are at position 3 and 5 of
the pyridine.

9. LANSOPRAZOLE:
Lansoprazole was the second of the PPI drugs to
reach the market, being launched in Europe in 1991
and the US in 1995. It has no substitutions at the
benzimidazole but two substituents on the pyridine:
 methyl group at position 3.
trifluoroethoxy group at position 4.
The drug is a 1:1 racemate of
the enantiomers dexlansoprazole and
levolansoprazole.

10. The story of pantoprazole's discovery is a good
example of the stepwise development of PPIs. The
main focus of modification of timoprazole was the
benzimidazole part of its structure. Addition of
a trifluoromethyl group to the
benzimidazole moiety led to a series of very active
compounds with varying solution-stability. In general
fluoro substituents were found to
block metabolism at the point where they were
attached. Later the more balanced fluoroalkoxy
substituent, instead of the highly lipophilic and
strongly electron-withdrawing trifluoromethyl
substituent, led to highly active compounds with
supposed longer half-lives and higher solution
stability.

11. PANTOPRAZOLE:
Pantoprazole was the third PPI and was introduced
to the German market in 1994. It has a
difluoroalkoxy sidegroup on the benzimidazole part
and two methoxy groups in position 3 and 4 on the
pyridine. Pantoprazole was first prepared in April
1985 by a small group of scale-up chemists.

12. RABEPRAZOLE:
Rabeprazole is a novel benzimidazole compound on
market, since 1999 in USA. It is similar to lansoprazole
in having no substituents on its benzimidazole part
and a methyl group at site 3 on the pyridine, the only
difference is the:
methoxypropoxy substitution at site 4 instead of the
trifluoroethoxy group on lansoprazole. Rabeprazole is
marketed as rabeprazole sodium salt.

13. DEVELOPMENT OF ESOMEPRAZOLE
Omeprazole showed an inter-individual variability and
therefore a significant number of patients with acid-related
disorders required higher or multiple doses to achieve
symptom relief and healing. Astra started a new research
program in 1987 to identify a new analogue to omeprazole
with less interpatient variability. Only one compound proved
superior to omeprazole and that was the S-isomer,
esomeprazole, which was developed as the magnesium salt.

14. Esomeprazole magnesium (Nexium) received its first
approval in 2000 and provided more pronounced
inhibition of acid secretion and less inter-patient
variation compared to omeprazole. In 2004, Nexium
had already been used to treat over 200 million
patients.

15. DEXLANSOPRAZOLE:
Dexlansoprazole was launched as a follow up of
lansoprazole in 2009. dexlansoprazole is an R-
enantiomer of lansoprazole, marketed as Dexilant.
After oral appliance of the racemic lansoprazole, the
circulating drug is 80% dexlansoprazole. Moreover,
both enantiomers have similar effects on the proton
pump

16. IMIDAZOPYRIDINES:
Tenatoprazole
Tenatoprazole (TU-199), an imidazopyridine proton pump inhibitor, is
a novel compound that has been designed as a new chemical entity
with a substantially prolonged plasma half-life (7h), but otherwise
has similar activity as other PPIs. The difference in the structural
backbone of tenatoprazole compared to benzimidazole PPIs, is its
imidazo[4,5-b]pyridine moiety, which reduces the rate of
metabolism, allowing a longer plasma residence time but also
decreases the pKa of the fused imidazole N as compared to the
current PPIs.

17. Tenatoprazole has the same substituents as omeprazole, the
methoxy groups at position 6 on the imidazopyridine and at
position 4 on the pyridine part as well as two methyl groups at
position 3 and 5 on the pyridine. The bioavailability of
tenatoprazole is double for the S-tenatoprazole sodium
salt hydrate form when compared to the free form in dogs. This
increased bioavailability is due to differences in the crystal
structure and hydrophobic nature of the two forms, and
therefore its more likely to be marketed as the pure S-
enantiomer

18. *THANK YOU