Discovery of isoquinolinone indole acetic acids as antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of …

…, J Thomason, A Huang, A Moretto, K Janz…

Index: Kaila, Neelu; Follows, Bruce; Leung, Louis; Thomason, Jennifer; Huang, Adrian; Moretto, Alessandro; Janz, Kristin; Lowe, Michael; Mansour, Tarek S.; Hubeau, Cedric; Page, Karen; Morgan, Paul; Fish, Susan; Xu, Xin; Williams, Cara; Saiah, Eddine Journal of Medicinal Chemistry, 2014 , vol. 57, # 4 p. 1299 - 1322

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Citation Number: 10

Abstract

Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents ...