Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1.
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).
Rist
Øystein
Ø
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
Grimstrup
Marie
M
Receveur
Jean-Marie
JM
Frimurer
Thomas M
TM
Ulven
Trond
T
Kostenis
Evi
E
Högberg
Thomas
T
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
D019151:Peptide Library; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013844:Thiazoles; D019342:Acetic Acid; C036293:prostaglandin D2 receptor