Identification of 1-{2-[4-chloro-1′-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4′-piperidine]-1-yl] phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y1 antagonist as an antiplatelet agent

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y(1) receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spi-ropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y(1) antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y(12) antagonist clopidogrel in rat efficacy/bleeding models. (C) 2014 Elsevier Ltd. All rights reserved.