title: 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.
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.
authors.affiliation: CVGI Medicinal Chemistry, ‡CVGI Bioscience, and §CVGI iMED Project Management, AstraZeneca R&D Mölndal , Pepparedsleden 1, S-43183 Mölndal, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Bach
authors.forename: Thomas
authors.initials: T
authors.lastname: Antonsson
authors.forename: Ruth
authors.initials: R
authors.lastname: Bylund
authors.forename: Jan-Arne
authors.initials: JA
authors.lastname: Björkman
authors.forename: Krister
authors.initials: K
authors.lastname: Österlund
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.forename: J J J
authors.initials: JJ
authors.lastname: van Giezen
authors.forename: Søren M
authors.initials: SM
authors.lastname: Andersen
authors.forename: Helen
authors.initials: H
authors.lastname: Zachrisson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Zetterberg
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D009525:Niacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: C548576:P2RY12 protein, human; D058925:Receptors, Purinergic P2Y12; D013449:Sulfonamides; C584249:ethyl 6-(4-((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-isopropylnicotinate; D009525:Niacin