Background: Recently, we reported ethyl nicotinates as antagonists of the P2Y₁₂ receptor, which is an important target in antiplatelet therapies. A potential liability of these compounds was their generally high in vivo clearance due to ethyl ester hydrolysis. Results: Shape and electrostatic similarity matching was used to select five-membered heterocycles to replace the ethyl ester functionality. The 5-methyl and 5-ethyl-oxazole bioisosteres retained the sub-micromolar potency levels of the parent ethyl esters. Many oxazoles showed a higher CYP450 dependent microsomal metabolism than the corresponding ethyl esters. Structure activity relationship investigations supported by ab initio calculations suggested that a correctly positioned alkyl substituent and a strong hydrogen bond acceptor were necessary structural motifs for binding. In rat pharmacokinetics, the low clearance was retained upon replacement of an ethyl ester with a 5-ethyl-oxazole. Conclusion: The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.