5-Alkyl-1,3-Oxazole Derivatives of 6-Amino-Nicotinic Acids as Alkyl Ester Bioisosteres are Antagonists of the P2Y 12 Receptor

Abstract

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. 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. The use of shape and electrostatic similarity led to the successful replacement of a metabolically labile ethyl ester functionality with 5-alkyl-oxazole bioisosteres.