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The discovery of Evogliptin was
inspired by B-amino acid thiazolidides11 and substituted piperazines. (Brockunier
et al., 2004)

Target compounds 4 and 5 were
made from Boc protected B amino acid and substituted heterocyclic amines via
the use of standard peptide coupling and deprotection of amine. A compound 7 was
produced by coupling of Boc-protected-priperizin-2-one with alkyl or aryl
halide. Another 8 compound was produced by deprotection of Boc derivatives
amongst hydrogen chloride in ether. Methyl 4a lead to an inhibition of DPP-4. Potency
was increased by a twofold more than methyl by five-membered hetero fusion
rings 4d and bi-phenyl 4c. This lead to a conclusion that there were
limitations with the activity elevation. Furthermore the essential moiety was
considered to be the benzyl 4f which is capable of producing hydrophobic interactions
with a side chain of Phe357. (Oefner et al.,
2003), (Kim et al., 2005), (Aertgeerts, 2004)

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This prompted further study on
benzyl moiety and lead to an introduction of a number of substituents. A distinction
was drawn showing that the nitro group ortho-4h had a higher potency in
comparison to para-4g. This resulted in further examination of the ortho-nitro

A decrease in inhibition
activity of 3- to 4- fold occurred from substituting of the nitro group to
electron-withdrawing cyano 4i or trifluoromethyl 4j. A high inhibitory
activity was achieved through tweaking of the ortho position substituent to
nitro group, and an extra substitution of methoxy to meta and para 4q. Preparations
of the substituted heterocyclic amine 18 were made.

An N-protected aziridine
compound 9 produced compound 10 through a series of reactions with alcohols,
amines and thiol. Subsequently deprotection occurred via the use of Pd/C and
hydrogen gas which lead to compound 11 which was altered by condensation with
Boc-amino acetaldehyde leading to compound 12.  This compound was than protected with Cbz and
deprotection of Boc took place which lead to the production of compound 13. Trimethyl
aluminium was used and further deprotection took place to produce compound 15.
Furthermore compound 5a was made from D-serine methyl ester. New start points
of hydroxyl derivatives were set which were in correlation to the number of the
alkyl size. It was found that addition of tert-butyl to (r)-hydroxy moiety 5f
was very potent. Oxygen was replaced in the hydrogen linker to nitrogen. Sulphur
was absorbed as a substitute rather than oxygen for hydroxy which lead to a
very potent DPP 4 inhibitory activity. The compound 5f was selected for further
examination with regards to its in vivo efficacy. Tests were conducted on rats
which showed compound 5f to inhibit DPP4 activity in under 30 minutes of
consumption. Another test was conducted which found compound 5f inhibited the increase
of blood glucose as well as decreasing the glucose AUC.

This study displayed how
variations of B-amino amide containing piperazine-2-one scaffold used in
compound 5f shows high DPP 4 inhibitory activity, in vivo efficacy and is safe
to use. As a result of this, compound 5f was sent for advance testing and is
now approved for commercial use and is known as Evogliptin. (Kim and Egan,
2008) (Kim et al., 2011)

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