The discovery of Sitagliptin is a story of finding an amide isostere that worked, then optimisation of pharmacokinetics via some fluorines in the right place. Metabolically labile amides can be replaced 5 membered heterocycles, where a lone pair of an aromatic N mimics the H-bonding of an amide carbonyl. Here the scientists at Pfizer combined this by “fusing” the five membered ring into a piperazine to generate a novel heterocycle. The rest of the optimisation was finding a CF3 group was optimal for bio-availability, although the reason for this is not clear. Interestingly, a pattern of fluorine atoms on the end benzene ring enhanced binding, and subsequent x-ray structure determination of the molecule bound to protein showed how good the fit was.
SITAGLIPTIN[MK-0431] (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
J. Med. Chem. 2005, 48, 1, 141–151
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