amg-009 and Asthma

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.

Topics: Asthma; Chemistry, Pharmaceutical; Drug Design; Humans; Hypersensitivity; Inhibitory Concentration 50; Kinetics; Models, Chemical; Phenylacetates; Prostaglandin D2; Receptors, G-Protein-Coupled; Receptors, Immunologic; Receptors, Prostaglandin; Sulfonamides

A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate.

Topics: Animals; Asthma; Drug Design; Humans; Receptors, Prostaglandin; Structure-Activity Relationship; Th2 Cells