title: Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 2.
abstract: Structure-activity relationships have been established by exploring the eastern and western side of 5-thiazolyleacetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Benzhydryl motifs in the 2-position of the thiazole was found to be most advantageous. The 4-thiazole position should either carry 3- or 4-fluorophenyl rings or a 4-pyridyl suitably substituted in the flanking 2-position. Several compounds with single digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained. The compound series display a good PK profile and selectivity over a large number of other targets.
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Grimstrup
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rist
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Receveur
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
authors.forename: Jesper M
authors.initials: JM
authors.lastname: Mathiesen
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: D019342:Acetic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D019151:Peptide Library; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018418:Th2 Cells; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019151:Peptide Library; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013844:Thiazoles; D019342:Acetic Acid; C036293:prostaglandin D2 receptor