amg-009 and phenylacetic-acid

Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI.

Topics: Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Indoles; Molecular Structure; Phenylacetates; Receptors, Immunologic; Receptors, Prostaglandin; Structure-Activity Relationship; Time Factors

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

Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15.

Topics: Drug Design; HEK293 Cells; Humans; Inhibitory Concentration 50; Molecular Structure; Phenylacetates; Protein Binding; Receptors, Immunologic; Receptors, Prostaglandin