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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

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

Peter Bach, Thomas Antonsson, Ruth Bylund, Jan-Arne Björkman, Krister Österlund, Fabrizio Giordanetto, J J J van Giezen, Søren M Andersen, Helen Zachrisson, Fredrik Zetterberg

J Med Chem. 2013 Sep 12;56(17):7015-24.

PMID: 23899349

Abstract:

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 3 and azetidine 13 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 3 and 13, respectively. Thus, the therapeutic index (TI) was ≥ 10 for both compounds. On the basis of these data, compound 3 was progressed into human clinical trials as candidate drug AZD1283.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP919351410	AZD1283		919351-41-0	Price

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