Recently, we described pyrazol-3-yl amino nicotinonitrile (AZ960  ) as an ATP-competitive Jak2 inhibitor where the pyrazol-3-yl amine group occupies the ATP binding site and interacts via hydrogen bonds with the Jak2 hinge. The suggested binding motif of three hydrogen bond interactions in a cis-donor/acceptor/donor fashion is believed to be possible because of an intra-molecular hydrogen bond between the C4-H of the pyrazole and the adjacent nitrogen of the pyridine ring.Further we showed that locking the two rings in a co-planar conformation to permit efficient interaction of the hinge binder with the protein backbone can also be accomplished by an isosteric replacement of the pyrazole ring with thiazole.  Here co-planarity is sustained viaa favorable electrostatic interaction between the nitrogen (d-) of the B-ring and the sulfur of the thiazole (d+).In this presentation a general account for the role of sulfur in conformation aspects of drug design will be discussed and how the use of sulfur-containing molecules in medicinal chemistry permits optimal interactions with targeted proteins.

Conformational aspects of sulfur in drug design

246th National Meeting (2013)

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