Lead Optimization of Ethyl 6‑Aminonicotinate Acyl Sulfonamides as Antagonists of the P2Y₁₂ Receptor. Separation of the Antithrombotic Effect and Bleeding for Candidate Drug AZD1283

Synthesis and structure–activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y₁₂ receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines. In a modified Folts model in dog, both piperidine <b>3</b> and azetidine <b>13</b> dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED₅₀ values of 3.0 and 10 μg/kg/min, respectively. The doses that induced a larger than 3-fold increase in bleeding time were 33 and 100 μg/kg/min for <b>3</b> and <b>13</b>, respectively. Thus, the therapeutic index (TI) was ≥10 for both compounds. On the basis of these data, compound <b>3</b> was progressed into human clinical trials as candidate drug AZD1283