Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1

Oystein Rist, Marie Grimstrup, Jean-Marie Receveur, Thomas M Frimurer, Trond Ulven, Evi Kostenis, Thomas Högberg

Research output: Contribution to journalJournal articleResearchpeer-review

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 66nM in a BRET and 12nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27muM in cAMP).
Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Volume20
Issue number3
Pages (from-to)1177-1180
ISSN0960-894X
DOIs
Publication statusPublished - 4. Dec 2009

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