Lead Optimization
of Ethyl 6‑Aminonicotinate
Acyl Sulfonamides as Antagonists of the P2Y<sub>12</sub> Receptor.
Separation of the Antithrombotic Effect and Bleeding for Candidate
Drug AZD1283
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Abstract
Synthesis and structure–activity
relationships of ethyl
6-aminonicotinate acyl sulfonamides, which are potent antagonists
of the P2Y<sub>12</sub> 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 ED<sub>50</sub> 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