Optimization of phenylacetic acid derivatives for CRTH2 and DP selective antagonism

Yingcai Wang; Zice Fu; Michael Schmitt; Xuemei Wang; Wang Shen; Erika Rickel; Tod Martin; Alison Budelsky; Derek Marshall; Tassie Collins; H Lucy Tang; Julio C Medina; Jiwen Jim Liu

doi:10.1016/j.bmcl.2011.10.123

Optimization of phenylacetic acid derivatives for CRTH2 and DP selective antagonism

Bioorg Med Chem Lett. 2012 Jan 1;22(1):367-70. doi: 10.1016/j.bmcl.2011.10.123. Epub 2011 Nov 9.

Authors

Yingcai Wang¹, Zice Fu, Michael Schmitt, Xuemei Wang, Wang Shen, Erika Rickel, Tod Martin, Alison Budelsky, Derek Marshall, Tassie Collins, H Lucy Tang, Julio C Medina, Jiwen Jim Liu

Affiliation

¹ Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

PMID: 22119474
DOI: 10.1016/j.bmcl.2011.10.123

Abstract

We have previously reported that optimization of a series of phenylacetic acid derivatives led to the discovery of CRTH2 and DP dual antagonists, such as AMG 009 and AMG 853. During the optimization process, we discovered that minor structural modifications also afforded potent and selective CRTH2 or DP antagonists. Here we report the structure-activity relationship that led to the discovery of selective CRTH2 antagonists such as 2 and 17, and selective DP antagonists, such as 4 and 5.

MeSH terms

Asthma / therapy
Chemistry, Pharmaceutical / methods
Drug Design
Humans
Hypersensitivity / drug therapy
Inhibitory Concentration 50
Kinetics
Models, Chemical
Phenylacetates / chemistry
Phenylacetates / pharmacology
Prostaglandin D2 / metabolism
Receptors, G-Protein-Coupled / metabolism
Receptors, Immunologic / antagonists & inhibitors*
Receptors, Prostaglandin / antagonists & inhibitors*
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

AMG 009
Phenylacetates
Receptors, G-Protein-Coupled
Receptors, Immunologic
Receptors, Prostaglandin
Sulfonamides
vidupiprant
phenylacetic acid
Prostaglandin D2
prostaglandin D2 receptor