Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD(2) receptors CRTH2 and DP

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 13; pp. 2877 - 2880
• Main Authors: Johnson, Michael G, Liu, Jim Jiwen, Li, An-Rong, van Lengerich, Bettina, Wang, Sophie, Medina, Julio C, Collins, Tassie L, Danao, Jay, Seitz, Lisa, Willee, Angela, D'Souza, Warren, Budelsky, Alison L, Fan, Peter W, Wong, Simon G W
• Format: Journal Article
• Language: English
• Published: England 01-07-2014
• Subjects: Cytochrome P-450 CYP3A - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Indoles - chemistry; Indoles - pharmacology; Molecular Structure; Phenylacetates - chemistry; Phenylacetates - pharmacology; Receptors, Immunologic - antagonists & inhibitors; Receptors, Prostaglandin - antagonists & inhibitors; Structure-Activity Relationship; Time Factors; CRTH2; Phenylacetic acid; CYP3A4; DP; Indole
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2014.04.092

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.