title: Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1.
abstract: Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional antagonistic effect of 66 nM in a BRET and 12 nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27 microM in cAMP).
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rist
authors.forename: Marie
authors.initials: M
authors.lastname: Grimstrup
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: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: D019342:Acetic Acid / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D019151:Peptide Library; D011485:Protein Binding / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019151:Peptide Library; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013844:Thiazoles; D019342:Acetic Acid; C036293:prostaglandin D2 receptor