Discovery of Isoquinolinone Indole Acetic Acids as Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases

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• 作者：Neelu Kaila ; Bruce Follows ; Louis Leung ; Jennifer Thomason ; Adrian Huang ; Alessandro Moretto ; Kristin Janz ; Michael Lowe ; Tarek S. Mansour ; Cedric Hubeau ; Karen Page ; Paul Morgan ; Susan Fish ; Xin Xu ; Cara Williams ; Eddine Saiah
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1299-1322
• 全文大小：1176K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

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 and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).