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

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

  • Bioorg Med Chem Lett. 2014 Jul 1;24(13):2877-80. doi: 10.1016/j.bmcl.2014.04.092.
Michael G Johnson 1,  Jim Jiwen Liu 2,  An-Rong Li 2,  Bettina van Lengerich 2,  Sophie Wang 2,  Julio C Medina 2,  Tassie L Collins 3,  Jay Danao 3,  Lisa Seitz 3,  Angela Willee 3,  Warren D'Souza 3,  Alison L Budelsky 3,  Peter W Fan 4,  Simon G W Wong 4
Affiliations

Affiliations

  • 1 Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA. Electronic address: mgjohnso@amgen.com.
  • 2 Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
  • 3 Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
  • 4 Department of Pharmacokinetics, Metabolism and Distribution, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
PMID: 24825301 DOI: 10.1016/j.bmcl.2014.04.092
Abstract

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.

Keywords

CRTH2; CYP3A4; DP; Indole; Phenylacetic acid.

Figures
Products