Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD2 receptors CRTH2 and DP |
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| Affiliation: | 1. Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA;2. Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA;3. Department of Pharmacokinetics, Metabolism and Distribution, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA;1. Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States;2. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States;3. Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Groton, CT 06340, United States;4. Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research & Development, Groton, CT 06340, United States;1. G.K. Boreskov Institute of Catalysis, SB RAS, Acad. Lavrentjev Ave. 5, 630090 Novosibirsk, Russian Federation;2. N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, SB RAS, Acad. Lavrentjev Ave. 9, 630090 Novosibirsk, Russian Federation;1. Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki City, Kagawa 769-2193, Japan;2. Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan;3. Division of Organic Chemistry, National Institute of Health Sciences, 1-18 Kamiyoga 1-Chome, Setagaya, Tokyo 158-8501, Japan |
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| 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. |
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| Keywords: | CRTH2 DP CYP3A4 Indole Phenylacetic acid |
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