Alogliptin, was provided by substitution of the central ring

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
was,
7-(2-chlorobenzyl)-1,3-dimethyl-8-(piperazin1-yl)-1H-purine-2,6(3H,7H)-dione.
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)

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