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
| Autor: | Ruth Bylund, Jan-Arne Björkman, J.J.J. van Giezen, Thomas Antonsson, Fabrizio Giordanetto, Søren M. Andersen, Fredrik Zetterberg, Krister Österlund, Peter Bach, Helen Zachrisson |
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| Rok vydání: | 2013 |
| Předmět: |
Sulfonamides
medicine.diagnostic_test Chemistry Azetidine Thrombosis CHO Cells Pharmacology Niacin Receptors Purinergic P2Y12 chemistry.chemical_compound Cricetulus Dogs Therapeutic index Bleeding time In vivo Cricetinae Drug Discovery Antithrombotic medicine Animals Humans Molecular Medicine Potency Platelet ED50 |
| Zdroj: | Journal of Medicinal Chemistry. 56:7015-7024 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm400820m |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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