Alogliptin, a pyrimidinedionebased potent and selective DPP 4 inhibitor was discovered by Syrrx (Takeda) inorder to treat patients suffering from type 2 diabetes.
There were a lot ofproblems faced prior to the development and discovery of Alogliptin. One of themain problems was to identify a suitable heterocyclic scaffold that could beused clinically. Alogliptin discovery begun from a xanthine derivative whichwas,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 fromhigh throughput crystallography. (Zhang et al., 2011) The 2-chlorobenzyl group hadbeen substituted by a 2-cyanobenzyl moiety, this caused a polar interactionbetween the cyano group and Arg125. Furthermore the piperazinyl group had beensubstituted by a 3-aminopiperidine moiety, this caused in increase in potency. Aselective and potent inhibitor was provided by substitution of the central ringby a quinazolinone scaffold which lead to inhibition of CP450 and hERGblockade.
In order to conquer these problems further SAR studies were conducted.Alogliptin was produced from substitution of the quinazoline ring by apyrimidinone moiety which changed to a pyrimidinedione ring. Another problemfaced was to discover the favoured stereochemistry at the C-3 position of theaminopiperidine moiety.
Prior to this the favoured R-stereochemistry was discoveredby preparation of both of the enantiomers of the xanthine-based inhibitor and testingthem for their in vitro inhibitory properties. Another issue which needed to besolved was the favoured orientation of the 3-amino group. The 3 amino groupfavoured an axial orientation on the piperidine ring which was discovered bythe co-complex of Alogliptin with the active site of DPP IV. Calculations suchas the ab initio which took place on the axial and equatorial conformationindicated a major stabilization of the axial conformation. This was as a resultof the nitrile amine interaction.
A chair form was displayed in the axialconformer and a boat form was noted in the equatorial conformer of the piperidinering. In conclusion task of the axial chair conformer aided by numerouscalculations had met the desired fit to the binding site. Once this was done andtoxicology assessments had been conducted to assess the in vivo profile ofAlogliptin in rats and dogs, Alogliptin had been considered for developmentclinically. (Parsa and Pal, 2011)