| Autor: |
Bach P; CVGI Medicinal Chemistry, ‡CVGI Bioscience, and §CVGI iMED Project Management, AstraZeneca R&D Mölndal , Pepparedsleden 1, S-43183 Mölndal, Sweden., Antonsson T, Bylund R, Björkman JA, Österlund K, Giordanetto F, van Giezen JJ, Andersen SM, Zachrisson H, Zetterberg F |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2013 Sep 12; Vol. 56 (17), pp. 7015-24. Date of Electronic Publication: 2013 Aug 29. |
| DOI: |
10.1021/jm400820m |
| Abstrakt: |
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: |
MEDLINE |
| Externí odkaz: |
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