title: 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.
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 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).
authors: Pfizer Research and Development , Cambridge, Massachusetts 02140, United States.
authors: Neelu
authors: N
authors: Kaila
authors: Bruce
authors: B
authors: Follows
authors: Louis
authors: L
authors: Leung
authors: Jennifer
authors: J
authors: Thomason
authors: Adrian
authors: A
authors: Huang
authors: Alessandro
authors: A
authors: Moretto
authors: Kristin
authors: K
authors: Janz
authors: Michael
authors: M
authors: Lowe
authors: Tarek S
authors: TS
authors: Mansour
authors: Cedric
authors: C
authors: Hubeau
authors: Karen
authors: K
authors: Page
authors: Paul
authors: P
authors: Morgan
authors: Susan
authors: S
authors: Fish
authors: Xin
authors: X
authors: Xu
authors: Cara
authors: C
authors: Williams
authors: Eddine
authors: E
authors: Saiah
mesh_terms: D000085:Acetates / Q000737:chemistry*; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D018418:Th2 Cells
chemical_list: D000085:Acetates; D015363:Quinolones; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor