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

doi:10.1016/j.bmcl.2009.12.008

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

12 Citations (Scopus)

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 language	English
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	20
Issue number	3
Pages (from-to)	1177-1180
Number of pages	4
ISSN	0960-894X
DOIs	https://doi.org/10.1016/j.bmcl.2009.12.008
Publication status	Published - 4 Dec 2009

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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 66nM in a BRET and 12nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27muM in cAMP).",

author = "Oystein Rist and Marie Grimstrup and Jean-Marie Receveur and Frimurer, {Thomas M} and Trond Ulven and Evi Kostenis and Thomas H{\"o}gberg",

year = "2009",

month = dec,

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doi = "10.1016/j.bmcl.2009.12.008",

language = "English",

volume = "20",

pages = "1177--1180",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Pergamon Press",

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TY - JOUR

T1 - Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1

AU - Rist, Oystein

AU - Grimstrup, Marie

AU - Receveur, Jean-Marie

AU - Frimurer, Thomas M

AU - Ulven, Trond

AU - Kostenis, Evi

AU - Högberg, Thomas

PY - 2009/12/4

Y1 - 2009/12/4

N2 - 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).

AB - 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).

U2 - 10.1016/j.bmcl.2009.12.008

DO - 10.1016/j.bmcl.2009.12.008

M3 - Journal article

SN - 0960-894X

VL - 20

SP - 1177

EP - 1180

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 3

ER -

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

Abstract

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