DL5050, a Selective Agonist for the Human Constitutive Androstane Receptor
- 12 June 2019
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Medicinal Chemistry Letters
- Vol. 10 (7), 1039-1044
- https://doi.org/10.1021/acsmedchemlett.9b00079
Abstract
The constitutive androstane receptor (CAR) is a xenobiotic sensor governing the transcription of genes involved in drug disposition, energy homeostasis, and cell proliferation. However, currently available human CAR (hCAR) agonists are nonselective, which commonly activate hCAR along with other nuclear receptors, especially the closely related human pregnane X receptor (hPXR). Using a well-known hCAR agonist CITCO as a template, we report our efforts in the discovery of a potent and highly selective hCAR agonist. Two of the new compounds of the series, 18 and 19 (DL5050), demonstrated excellent potency and selectivity for hCAR over hPXR. DL5050 preferentially induced the expression of CYP2B6 (target of hCAR) over CYP3A4 (target of hPXR) on both the mRNA and protein levels. The selective hCAR agonist DL5050 represents a valuable tool molecule to further define the biological functions of hCAR, and may also be used as a new lead in the discovery of hCAR agonists for various therapeutic applications.Keywords
Funding Information
- National Center for Advancing Translational Sciences
- National Institute of General Medical Sciences (GM107058, GM121550)
- Maryland Innovation Initiative
This publication has 38 references indexed in Scilit:
- The Nuclear Pregnane X Receptor: A Key Regulator of Xenobiotic MetabolismEndocrine Reviews, 2002
- Nuclear Pregnane X Receptor and Constitutive Androstane Receptor Regulate Overlapping but Distinct Sets of Genes Involved in Xenobiotic DetoxificationMolecular Pharmacology, 2002
- Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and Benzoate X Receptor (BXR) Define Three Pharmacologically Distinct Classes of Nuclear ReceptorsMolecular Endocrinology, 2002
- Pxr, car and drug metabolismNature Reviews Drug Discovery, 2002
- An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acidsProceedings of the National Academy of Sciences of the United States of America, 2001
- Role reversal: new insights from new ligands for the xenobiotic receptor CARTrends in Endocrinology & Metabolism, 2001
- The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolismNature, 2000
- Humanized xenobiotic response in mice expressing nuclear receptor SXRNature, 2000
- Orphan Nuclear Receptors Constitutive Androstane Receptor and Pregnane X Receptor Share Xenobiotic and Steroid LigandsPublished by Elsevier BV ,2000
- Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamideBiochemical Pharmacology, 2000