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

• Published in: Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.1177-1180
• Main Authors: Rist, Øystein, Grimstrup, Marie, Receveur, Jean-Marie, Frimurer, Thomas M., Ulven, Trond, Kostenis, Evi, Högberg, Thomas
• Format: Article
• Language: English
• Subjects: Acetic Acid - chemical synthesis; Acetic Acid - metabolism; Acetic Acid - pharmacology; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cercopithecus aethiops; COS Cells; Humans; Medical sciences; Peptide Library; Pharmacology. Drug treatments; Protein Binding - physiology; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin - metabolism; Respiratory system; Thiazoles - chemical synthesis; Thiazoles - metabolism; Thiazoles - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.12.008

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 3.7 nM 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 μM in cAMP).