Before the days of high through screening, starting from the natural substrate was the method of generating chemical leads for drug discovery. Beginning with ATP, a quite poor lead for an oral programme, a potent P2Y12 antagonists with found. Remarkably all the elements in the medicinal chemical journey have been crammed into this BMCL paper! Of note is the replacement of the labile triphosphate group and increasing affinity with a triazolopyrimidine core and introducing a trans-2-phenylcyclopropylamino substituent. The resultant drug Ticagrelor is quite complex and the manufacturing route is whole other story too.
From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis.
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