Avoiding PXR and CAR Activation and CYP3A4 Enzyme Induction

Sinz, Michael

doi:10.1007/7355_2013_24

Cited by 6 publications

(7 citation statements)

References 74 publications

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“…Unexpectedly, 1.5-fold increase in liver exposure of 56 was observed at the dose of 200 mg/kg 67 comparing with that at 100 mg/kg (Table ). One possibility was that a high concentration of the compound induced the metabolic enzyme overexpression . These results proved the advantage of amino acid prodrug in improving the exposure and in vivo anti-HBV efficacy of (1 H -pyrazolo[3,4- c ]pyridin-5-yl)sulfonamide derivative 56 .…”

Section: Resultsmentioning

confidence: 88%

Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

et al. 2020

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Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC 50 value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.

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Section: Resultsmentioning

confidence: 88%

Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

et al. 2020

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“…Previous reports using mRNA and protein assessment in primary human hepatocytes, HepG2 cells, and reporter assays revealed that CYP2B6, CYP3A4, and UGT1A1 gene expression was coregulated by PXR and CAR (Honkakoski et al, 1998;Goodwin et al, 2001;Sugatani et al, 2005;Sinz et al, 2006;Sinz, 2015). In addition, the induction of UGT1A1 gene expression in human hepatoma HepG2 cells has been noted with AhR activation (Yueh et al, 2003).…”

Section: Discussionmentioning

confidence: 97%

Establishing Transcriptional Signatures to Differentiate PXR-, CAR-, and AhR-Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes

Moscovitz

Kalgutkar

Nulick

et al. 2018

J Pharmacol Exp Ther

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The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug-disposition genes via activation of nuclear receptors (NRs), such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR), remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR-/CAR-/AhR-specific drug-metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO), and AhR (omeprazole). Dose response for ligand-induced changes to 38 major human DMEs and critical hepatobiliary transporters were assessed using a custom gene expression array card. We identified novel differentially expressed drug-disposition genes for PXR (↑ABCB1/MDR1, CYP2C9, CYP2C19, and EPHX1, ↓ABCB11), CAR [↑sulfotransferase (SULT) 1E1, uridine glucuronosyl transferase (UGT) 2B4], and AhR (↑SLC10A1/NTCP, SLCO1B1/OATP1B1], and coregulated genes (CYP1A1, CYP2B6, CYP2C8, CYP3A4, UGT1A1, UGT1A4). Subsequently, DME gene expression signatures were generated for known CYP3A4 inducers PF-06282999 and pazopanib. The former produced an induction signature almost identical to that of rifampin, suggesting activation of the PXR pathway, whereas the latter produced an expression signature distinct from those of PXR, CAR, or AhR, suggesting involvement of an alternate pathway(s). These results demonstrate that involvement of PXR/CAR/AhR can be identified via expression changes of signature DME/transporter genes. Inclusion of such signature genes could serve to simultaneously identify potential inducers and inhibitors, and the NRs involved in the transcriptional regulation, thus providing a more holistic and mechanism-based assessment of DDI risk for DMEs and transporters beyond conventional cytochrome P450 isoforms.

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“…The well adopted strategies to reduce hPXR activation include (1) introducing a polar substituent to the lipophilic group to destabilize the hydrophobic interactions and (2) removing the central H-bond acceptor. 8,9 However, from the cocrystal structure of Cp149 Y132A mutant hexamer in complex with 1 (5WRE) (Figure 1a), both the C2 thiazoyl and the C4 phenyl were located in hydrophobic pockets, where introduction of polar substituent would essentially lead to a loss of binding affinity to core proteins. Moreover, the removal of potential H-bond acceptors, e.g., replacing the dihydropyr-imidine with dihydropyridine or C5 ester with trifluoromethyl, led to a complete loss of anti-HBV activity.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In the human PXR transactivation assay, both compounds 1 and 2 were found to be strong PXR activators, indicating PXR activation as the mechanism of CYP3A4 induction for this chemical class of capsid inhibitors. Several crystal structures of the human PXR ligand binding domain (LBD) complexed with structurally diversified PXR activators were reported, which revealed an unusually large and flexible binding pocket. , A plausible pharmacophore model of PXR activators was proposed, which comprised one H-bond acceptor and at least two flanking hydrophobic groups, in particular aromatic groups . The structure of the HAP class of capsid inhibitors represented by compounds 1 and 2 coincidently contains all the pharmacophore elements favorable for hPXR binding, in which the C2 thiazoyl and the C4 phenyl play the part of hydrophobic groups and the nitrogen of the dihydropyrimidine or the carbonyl oxygen of the C5 methyl ester accounts for the key H-bonding interaction with PXR, thus potentially explaining the strong CYP3A4 induction effect observed for both compounds 1 and 2 .…”

Section: Introductionmentioning

confidence: 99%

“…The structure of the HAP class of capsid inhibitors represented by compounds 1 and 2 coincidently contains all the pharmacophore elements favorable for hPXR binding, in which the C2 thiazoyl and the C4 phenyl play the part of hydrophobic groups and the nitrogen of the dihydropyrimidine or the carbonyl oxygen of the C5 methyl ester accounts for the key H-bonding interaction with PXR, thus potentially explaining the strong CYP3A4 induction effect observed for both compounds 1 and 2 . The well adopted strategies to reduce hPXR activation include (1) introducing a polar substituent to the lipophilic group to destabilize the hydrophobic interactions and (2) removing the central H-bond acceptor. , However, from the cocrystal structure of Cp149 Y132A mutant hexamer in complex with 1 (5WRE) (Figure a), both the C2 thiazoyl and the C4 phenyl were located in hydrophobic pockets, where introduction of polar substituent would essentially lead to a loss of binding affinity to core proteins. Moreover, the removal of potential H-bond acceptors, e.g., replacing the dihydropyrimidine with dihydropyridine or C5 ester with trifluoromethyl, led to a complete loss of anti-HBV activity.…”

Section: Introductionmentioning

confidence: 99%

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A New Approach of Mitigating CYP3A4 Induction Led to the Discovery of Potent Hepatitis B Virus (HBV) Capsid Inhibitor with Optimal ADMET Profiles

et al. 2019

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Described herein is a new approach to mitigate CYP3A4 induction. In this unconventional approach, a fine-tuning of the dihedral angle between the C4 phenyl and the dihydropyrimidine core of the heteroaryldihydropyrimidine (HAP) class of capsid inhibitors successfully altered the structure–activity−relationships (SARs) of the unwanted CYP3A4 induction and the desired HBV capsid inhibition to more favorable values. This eventually led to the discovery of a new capsid inhibitor with significantly reduced CYP3A4 induction, excellent anti-HBV activity, favorable preclinical PK/PD profiles, and no early safety flags.

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Avoiding PXR and CAR Activation and CYP3A4 Enzyme Induction

Cited by 6 publications

References 74 publications

Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

Establishing Transcriptional Signatures to Differentiate PXR-, CAR-, and AhR-Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes

A New Approach of Mitigating CYP3A4 Induction Led to the Discovery of Potent Hepatitis B Virus (HBV) Capsid Inhibitor with Optimal ADMET Profiles

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