ReseaRch aRticle The platelet P2Y 12 receptor plays an impor- tant role in the amplification phase of platelet aggregation [1]. It belongs to the P2 purinergic receptors [2], which include two major families of receptors in humans: the G protein-coupled or metabotropic P2Y receptors and the ligand-gated ion channels or ionotropic P2X receptors. Eight subtypes of the P2Y receptor and seven subtypes of the P2X receptor have been found in humans. Of these, blood platelets express the subtypes P2Y 1 and P2Y 12 , which are activated by ADP, and the subtype P2X 1 , which is activated by ATP [3]. When platelets are stimulated they release ADP from their dense-granules. Activation of the G q - coupled P2Y 1 receptors leads to increased levels of phospholipase C and mobilization of calcium ions from internal stores, while activation of the G i -coupled P2Y 12 receptors inhibits intracellular adenylyl cyclase activity [4]. Prolonged calcium signaling and decreased cAMP levels together stabilize the formed platelet aggregates. The central role of the P2Y 12 receptor in platelet function has made it an attractive tar- get for the development of novel anti-platelet aggregation therapies [5,6]. These include the thienopyridine prodrugs ticlopidine and clopi- dogrel, whose active metabolites bind irrevers- ibly to the receptor [7], and ticagrelor [8,9], the first reversibly binding, direct-acting P2Y 12 antagonist. Other examples of P2Y 12 antago- nists include piperazinylglutamate-pyridines and -pyrimidines [10–13], thienopyrimidines [14], anthraquinones [15], adenosine analogs [16], and dinucleoside polyphosphates and nucleotides [17]. Series of urea [18], sulfonylurea [19] and acyl sulfonamide [20] derivatives of ethyl nicotin- ates, exemplified by compounds 1–3 (FiguRe 1), are antagonists of the P2Y 12 receptor. A com- mon structural motif of these compounds is the ethyl ester functionality that may be prone to metabolism. One strategy to increase meta- bolic stability is to replace potentially labile functional groups with bioisosteres [21–23]. In order to pursue this idea, we investigated if the ethyl ester functionality could be replaced by heterocycles as nonclassical bioisosteres [24]. To prioritize the synthetic efforts, we employed our in-house-developed program ‘ItsElectric’ [25] to identify suitable heterocycles as bioisosteres of the ethyl ester, based on similarity in shape and electrostatics. Compounds in the series of bioisosteres, exemplified by compound 4 (FiguRe 1), were composed of a pyridine (A-ring), that was sub- stituted in the 3-position with an ethyl ester bioisostere and in the 6-position with a piper- azinyl, piperidinyl or azetidinyl (B-ring). The B-ring was joined via a sulfonylurea or an acyl sulfonamide linker (L) to a 5-chloro-2-thienyl or benzyl substituent (C-ring). Chemistry A- and B-rings were coupled by nucleophilic aro- matic substitution (S N Ar) reactions. The formed 5-alkyl-1,3-oxazole derivatives of 6-amino- nicotinic acids as alkyl ester bioisosteres are antagonists of the P2Y 12 receptor Background: Recently, we reported ethyl nicotinates as antagonists of the P2Y 12 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. Peter Bach*, Jonas Boström, Kay Brickmann, Laurence E Burgess, David Clarke, Robert D Groneberg, Darren M Harvey, Ellen R Laird, Michael O’Sullivan & Fredrik Zetterberg Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, S-43183 Mölndal, Sweden *Author for correspondence: E-mail: bach@chalmers.se 2037 ISSN 1756-8919 10.4155/FMC.13.171 © 2013 Future Science Ltd Future Med. Chem. (2013) 5(17), 2037–2056 For reprint orders, please contact reprints@future-science.com