The Disconnect in Intrinsic Clearance Determined in Human Hepatocytes and Liver Microsomes Results from Divergent Cytochrome P450 Activities

Bapiro, Tashinga E.; Martin, Scott E.; Wilkinson, Stephen D.; Orton, Alexandra L.; Hariparsad, Niresh; Harlfinger, Stephanie; McGinnity, Dermot F.

doi:10.1124/dmd.123.001323

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…1 E ). Furthermore, although there were some inconsistencies with the microsomal results [for which there are several potential explanations ( 28 )], this improvement was also seen with the approved medicine set ( Fig. 1 F ).…”

Section: Resultsmentioning

confidence: 75%

Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

MacLeod,

Coquelin,

Huertas

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here, we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily (“8HUM”) can circumvent these problems. The pharmacokinetics, metabolite profiles, and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis , Leishmania donovani, and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery.

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Section: Resultsmentioning

confidence: 75%

Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

MacLeod,

Coquelin,

Huertas

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…While the in vitro metabolic stability of compound 31 is suboptimal by the human liver microsome, its stability in human hepatocytes (HH 8.7) is a promising indicator of human clearance (Table 5). Since HH has been reported as a better predictor for doseto-man calculation, 31 this compound was progressed for further in vivo studies.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The resulting mixture was purified by C18 reversed-phase chromatography using 0−50% 0.2% aq ammonia in ACN to afford 29 (268 mg, 72%). 1 H NMR (500 MHz, DMSO-d 6 ): 1.07 (br d, J = 5.0 Hz, 3H), 2.53 (br s, 6H), 2.81−2.90 (m, 2H), 3.18 (s, 4H), 5.49 (s, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 8.26 (s, 1H), 8.60 (s, 1H) 2, (31). (E)-N 1 ,N 1 ,N 2 ,N 2 -Tetramethyldiazene-1,2-dicarboxamide (266 mg, 1.54 mmol) was added to a degassed mixture of 1-(1-methyl-1H-pyrazol-4-yl)ethan-1-ol (97 mg, 0.77 mmol), compound 9 (200 mg, 0.51 mmol), and tributylphosphine (0.4 mL, 1.54 mmol) in THF (5 mL) under nitrogen.…”

Section: Cyclobutyl)phenyl)-5-(trifluoromethyl)pyridin-2(1h)-one (21)mentioning

confidence: 99%

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

Mfuh,

Boerth,

Bommakanti

et al. 2024

J. Med. Chem.

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Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC 50 value of 30 nM and induces IL-2 production in T-cells with an EC 50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.

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Real-World Application of Physiologically Based Pharmacokinetics in Drug Discovery

Santos,

Jaiswal,

Chen

et al. 2024

Drug Metabolism and Disposition

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The utility of PBPK models in support of drug development has been well documented.During the discovery stage, PBPK has increasingly been applied for early risk assessment, prediction of human dose, toxicokinetic dose projection and early formulation assessment. Previous review articles have proposed model building and application strategies for PBPK-based first in human predictions with comprehensive descriptions of the individual components of PBPK models. This includes the generation of decision trees, based on comprehensive literature reviews, to guide the application of PBPK in the discovery setting. The goal of this mini review is to provide additional guidance on the real-world application of PBPK, in support of the discovery stage of drug development. In this mini review, our goal is to provide guidance on the typical steps involved in the development and application of a PBPK model during drug discovery to assist in decision making. We have illustrated our recommended approach through description of case examples, where PBPK has been successfully applied to aid in human PK projection, candidate selection and prediction of drug interaction liability for parent and metabolite. Through these case studies, we have highlighted fundamental issues, including pre-verification in preclinical species, the application of empirical scalars in the prediction of in vivo clearance from in vitro systems, in silico prediction of permeability and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed. Significance StatementThrough description of three case studies, we have highlighted the fundamental principles of PBPK application during drug discovery. These include pre-verification of the model in preclinical species, application of empirical scalars where necessary in the prediction of clearance, in silico prediction of permeability, and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed.

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The Disconnect in Intrinsic Clearance Determined in Human Hepatocytes and Liver Microsomes Results from Divergent Cytochrome P450 Activities

Cited by 4 publications

References 31 publications

Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

Real-World Application of Physiologically Based Pharmacokinetics in Drug Discovery

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