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  1. Article ; Online: Nonspecific Binding Considerations in the Rational Design and Development of Small Molecule COVID-19 Therapeutics.

    Maurer, Tristan S

    Clinical pharmacology and therapeutics

    2021  Volume 110, Issue 2, Page(s) 294–296

    MeSH term(s) Binding Sites ; COVID-19 ; Drug Design ; Humans ; SARS-CoV-2
    Language English
    Publishing date 2021-02-05
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.2159
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  2. Article ; Online: Quantitative Model-Based Assessment of Multiple Sickle Cell Disease Therapeutic Approaches Alone and in Combination.

    Moody, Amy T / Narula, Jatin / Maurer, Tristan S

    Clinical pharmacology and therapeutics

    2024  Volume 115, Issue 5, Page(s) 1114–1121

    Abstract: Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3-BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense-state sickle hemoglobin that ... ...

    Abstract Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3-BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense-state sickle hemoglobin that contributes to polymer formation. Induction of 30% HbF is seen as the gold standard because 30% endogenous expression is associated with a lack of symptoms. However, the level of intervention required to achieve equivalent polymerization protection by the other strategies is uncertain, and there is little understanding of how these approaches could work in combination. We sought to develop an oxygen saturation model that could assess polymerization protection of all three approaches alone or in combination by extending the Monod-Wymann-Changeux model to include additional mechanisms. Applying the model to monotherapies suggests 51% sickle hemoglobin (HbS) occupancy with an oxyHb stabilizer or lowering RBC 2,3 BPG concentrations to 1.8 mM would produce comparable polymerization protection as 30% HbF. The model predictions are consistent with observed clinical response to the oxyHb stabilizer voxelotor and the 2,3-BPG reducer etavopivat. The model also suggests combination therapy will have added benefit in the case of dose limitations, as is the case for voxelotor, which the model predicts could be combined with 20% HbF or 2,3-BPG reduction to 3.75 mM to reach equivalent protection as 30% HbF. The proposed model represents a unified framework that is useful in supporting decisions in preclinical and early clinical development and capable of evolving with clinical experience to gain new and increasingly confident insights into treatment strategies for SCD.
    MeSH term(s) Humans ; Hemoglobin, Sickle/therapeutic use ; Anemia, Sickle Cell/drug therapy ; Benzaldehydes/therapeutic use ; Pyrazines/therapeutic use ; Fetal Hemoglobin/metabolism ; Fetal Hemoglobin/therapeutic use ; Pyrazoles
    Chemical Substances Hemoglobin, Sickle ; voxelotor (3ZO554A4Q8) ; Benzaldehydes ; Pyrazines ; Fetal Hemoglobin (9034-63-3) ; Pyrazoles
    Language English
    Publishing date 2024-01-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.3175
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  3. Article: Editorial: Model-informed decision making in the preclinical stages of pharmaceutical research and development.

    Li, Rui / Craig, Morgan / D'Argenio, David Z / Betts, Alison / Mager, Donald E / Maurer, Tristan S

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1184914

    Language English
    Publishing date 2023-04-12
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1184914
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  4. Article ; Online: Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy.

    Tess, David A / Maurer, Tristan S / Li, Zhenhong / Bulawa, Christine / Fleming, James / Moody, Amy T

    Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis

    2022  Volume 30, Issue 2, Page(s) 208–219

    Abstract: Background: Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial ...

    Abstract Background: Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed.
    Methods: We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic-pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression.
    Results: Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation
    Conclusions: These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism.
    Clinicaltrials.gov identifier: NCT01994889.
    MeSH term(s) Humans ; Amyloid Neuropathies, Familial/drug therapy ; Amyloid Neuropathies, Familial/genetics ; Amyloid Neuropathies, Familial/complications ; Prealbumin/genetics ; Prealbumin/metabolism ; Benzoxazoles/therapeutic use ; Cardiomyopathies/metabolism ; Disease Progression
    Chemical Substances tafamidis (8FG9H9D31J) ; Prealbumin ; Benzoxazoles
    Language English
    Publishing date 2022-11-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 1205246-2
    ISSN 1744-2818 ; 1350-6129
    ISSN (online) 1744-2818
    ISSN 1350-6129
    DOI 10.1080/13506129.2022.2145876
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  5. Article ; Online: Theoretical Considerations for Direct Translation of Unbound Liver-to-Plasma Partition Coefficient from In Vitro to In Vivo.

    Li, Zhenhong / Di, Li / Maurer, Tristan S

    The AAPS journal

    2019  Volume 21, Issue 3, Page(s) 43

    Abstract: There is considerable interest in developing methods to predict the asymmetric distribution of unbound drug into tissues. The liver is of particular interest due to the multitude of expressed transporters with potential implications for pharmacokinetics, ...

    Abstract There is considerable interest in developing methods to predict the asymmetric distribution of unbound drug into tissues. The liver is of particular interest due to the multitude of expressed transporters with potential implications for pharmacokinetics, pharmacodynamics, and toxicology. Empirical correlations of in vitro unbound hepatocyte-to-media partition coefficient (in vitro K
    MeSH term(s) Animals ; Cell Line ; Hepatocytes/metabolism ; Humans ; Liver/metabolism ; Models, Biological ; Permeability ; Plasma/metabolism ; Rats ; Tissue Distribution
    Language English
    Publishing date 2019-03-18
    Publishing country United States
    Document type Journal Article
    ISSN 1550-7416
    ISSN (online) 1550-7416
    DOI 10.1208/s12248-019-0314-1
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  6. Article ; Online: Designing small molecules for therapeutic success: A contemporary perspective.

    Maurer, Tristan S / Edwards, Martin / Hepworth, David / Verhoest, Patrick / Allerton, Charlotte M N

    Drug discovery today

    2021  Volume 27, Issue 2, Page(s) 538–546

    Abstract: Successful small-molecule drug design requires a molecular target with inherent therapeutic potential and a molecule with the right properties to unlock its potential. Present-day drug design strategies have evolved to leave little room for improvement ... ...

    Abstract Successful small-molecule drug design requires a molecular target with inherent therapeutic potential and a molecule with the right properties to unlock its potential. Present-day drug design strategies have evolved to leave little room for improvement in drug-like properties. As a result, inadequate safety or efficacy associated with molecular targets now constitutes the primary cause of attrition in preclinical development through Phase II. This finding has led to a deeper focus on target selection. In this current reality, design tactics that enable rapid identification of risk-balanced clinical candidates, translation of clinical experience into meaningful differentiation strategies, and expansion of the druggable proteome represent significant levers by which drug designers can accelerate the discovery of the next generation of medicines.
    MeSH term(s) Drug Design
    Language English
    Publishing date 2021-09-30
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2021.09.017
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  7. Article ; Online: Dose Predictions for Drug Design.

    Maurer, Tristan S / Smith, Dennis / Beaumont, Kevin / Di, Li

    Journal of medicinal chemistry

    2020  Volume 63, Issue 12, Page(s) 6423–6435

    Abstract: The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose is predicted at many stages in drug discovery and development. Prior to the 1990s, dose prediction was limited to the drug "working" at a ... ...

    Abstract The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose is predicted at many stages in drug discovery and development. Prior to the 1990s, dose prediction was limited to the drug "working" at a reasonable dose and dose regimen in an animal model. Through the early 2000s, dose predictions were generated at candidate nomination and then refined during clinical development. Currently, dose predictions can be made early in drug discovery to enable drug design. Dose predictions at this stage can identify critical drug properties for a viable dose regimen and provide clinically relevant context to lead optimization. In this paper, we give an overview of the opportunities and challenges associated with dose prediction for drug design. A number of general considerations, approaches, and case examples are discussed.
    MeSH term(s) Animals ; Dose-Response Relationship, Drug ; Drug Design ; Drug Discovery ; Drug Evaluation, Preclinical ; Humans ; Pharmaceutical Preparations/chemistry ; Pharmaceutical Preparations/metabolism ; Pharmaceutical Preparations/standards
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2020-01-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.9b01365
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  8. Article ; Online: A Physiologically Based

    Li, Zhenhong / Litchfield, John / Tess, David A / Carlo, Anthony A / Eng, Heather / Keefer, Christopher / Maurer, Tristan S

    Journal of medicinal chemistry

    2020  Volume 63, Issue 12, Page(s) 6489–6498

    Abstract: Drug precipitation in the nephrons of the kidney can cause drug-induced crystal nephropathy (DICN). To aid mitigation of this risk in early drug discovery, we developed a physiologically ... ...

    Abstract Drug precipitation in the nephrons of the kidney can cause drug-induced crystal nephropathy (DICN). To aid mitigation of this risk in early drug discovery, we developed a physiologically based
    MeSH term(s) Animals ; Computer Simulation ; Dogs ; Drug Discovery ; Drug Evaluation, Preclinical ; Drugs, Investigational/adverse effects ; Humans ; Kidney Calculi/chemically induced ; Kidney Calculi/pathology ; Models, Biological ; Pharmaceutical Preparations/chemistry ; Pharmaceutical Preparations/metabolism ; Quantitative Structure-Activity Relationship ; Rats
    Chemical Substances Drugs, Investigational ; Pharmaceutical Preparations
    Language English
    Publishing date 2020-03-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.9b01995
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  9. Article ; Online: Unbound Brain-to-Plasma Partition Coefficient, K

    Loryan, Irena / Reichel, Andreas / Feng, Bo / Bundgaard, Christoffer / Shaffer, Christopher / Kalvass, Cory / Bednarczyk, Dallas / Morrison, Denise / Lesuisse, Dominique / Hoppe, Edmund / Terstappen, Georg C / Fischer, Holger / Di, Li / Colclough, Nicola / Summerfield, Scott / Buckley, Stephen T / Maurer, Tristan S / Fridén, Markus

    Pharmaceutical research

    2022  Volume 39, Issue 7, Page(s) 1321–1341

    Abstract: Purpose: More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (K: Methods: To understand the importance and impact of the K: Results and conclusions: From the responses, it is clear that ... ...

    Abstract Purpose: More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (K
    Methods: To understand the importance and impact of the K
    Results and conclusions: From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of K
    MeSH term(s) Blood-Brain Barrier ; Brain ; Central Nervous System Agents ; Drug Discovery/methods ; Humans
    Chemical Substances Central Nervous System Agents
    Language English
    Publishing date 2022-04-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 843063-9
    ISSN 1573-904X ; 0724-8741 ; 0739-0742
    ISSN (online) 1573-904X
    ISSN 0724-8741 ; 0739-0742
    DOI 10.1007/s11095-022-03246-6
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  10. Article ; Online: Clearance in Drug Design.

    Smith, Dennis A / Beaumont, Kevin / Maurer, Tristan S / Di, Li

    Journal of medicinal chemistry

    2018  Volume 62, Issue 5, Page(s) 2245–2255

    Abstract: Due to its implications for both dose level and frequency, clearance rate is one of the most important pharmacokinetic parameters to consider in the design of drug candidates. Clearance can be classified into three general categories, namely, metabolic ... ...

    Abstract Due to its implications for both dose level and frequency, clearance rate is one of the most important pharmacokinetic parameters to consider in the design of drug candidates. Clearance can be classified into three general categories, namely, metabolic transformation, renal excretion, and hepatobiliary excretion. Within each category, there are a host of biochemical and physiological mechanisms that ultimately determine the clearance rate. Physiochemical properties are often indicative of the rate-determining mechanism, with lipophilic molecules tending toward metabolism and hydrophilic, polar molecules tending toward passive or active excretion. Optimization of clearance requires recognition of the major clearance mechanisms and use of the most relevant in vitro and in vivo tools to develop structure-clearance relationships. The reliability of methods to detect and predict human clearance varies across mechanisms. While methods for metabolic and passive renal clearance have proven reasonably robust, there is a clear need for better tools to support the optimization of transporter-mediated clearance.
    MeSH term(s) Animals ; Drug Design ; Humans ; Hydrophobic and Hydrophilic Interactions ; Kidney/metabolism ; Liver/metabolism ; Membrane Transport Proteins/metabolism ; Metabolic Clearance Rate ; Pharmaceutical Preparations/metabolism ; Structure-Activity Relationship
    Chemical Substances Membrane Transport Proteins ; Pharmaceutical Preparations
    Language English
    Publishing date 2018-10-17
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.8b01263
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