Skip to Content
Merck
  • 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.

Journal of medicinal chemistry (2013-08-01)
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
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Nicotinic acid, analytical standard
Sigma-Aldrich
Nicotinic acid, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥98%
Sigma-Aldrich
Nicotinic acid, ≥98%
Sigma-Aldrich
Nicotinic acid, meets USP testing specifications
Supelco
Niacin (Nicotinic Acid), Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Nicotinic acid, ≥99.5% (HPLC)
Sigma-Aldrich
AZD1283, ≥98% (HPLC)