title: Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981.
abstract: Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK. tim.luker@astrazeneca.com
authors.forename: Tim
authors.initials: T
authors.lastname: Luker
authors.forename: Roger
authors.initials: R
authors.lastname: Bonnert
authors.forename: Steve
authors.initials: S
authors.lastname: Brough
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Cook
authors.forename: Mark R
authors.initials: MR
authors.lastname: Dickinson
authors.forename: Iain
authors.initials: I
authors.lastname: Dougall
authors.forename: Chris
authors.initials: C
authors.lastname: Logan
authors.forename: Rukhsana T
authors.initials: RT
authors.lastname: Mohammed
authors.forename: Stuart
authors.initials: S
authors.lastname: Paine
authors.forename: Hitesh J
authors.initials: HJ
authors.lastname: Sanganee
authors.forename: Carol
authors.initials: C
authors.lastname: Sargent
authors.forename: Jerzy A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: Simon
authors.initials: S
authors.lastname: Teague
authors.forename: Stephen
authors.initials: S
authors.lastname: Thom
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*
chemical_list: D000085:Acetates; D007210:Indoleacetic Acids; D007211:Indoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C569518:AZD1981; C036293:prostaglandin D2 receptor