Preclinical Research Overview - Lead generation and Optimisation Flashcards

1
Q

What is the main goal of lead optimization in drug development?

A

The main goal of lead optimization is to enhance the most promising drug candidates by improving their effectiveness, reducing toxicity, and increasing absorption.

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2
Q

What does the term “therapeutic index” (TI) refer to?

A

The therapeutic index is a measure of a drug’s safety, indicating the range between effective and toxic doses. A higher TI suggests a larger window for the drug’s therapeutic effect.

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3
Q

How can efficacy be assessed during lead optimization?

A

Efficacy can be measured using animal models that simulate human diseases, allowing researchers to evaluate how well lead-optimized compounds perform in a living organism.

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4
Q

What does the acronym ADME stand for, and why is it important?

A

ADME stands for Absorption, Distribution, Metabolism, and Excretion. It is important because these pharmacokinetic properties influence a drug’s effectiveness and safety in the body.

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5
Q

What are the four components of ADME?

A

Absorption: Movement of a drug from its administration site into the bloodstream.
Distribution: Movement of the drug throughout the body.
Metabolism: Transformation of the drug into metabolites.
Excretion: Removal of the drug from the body.

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6
Q

What role does in vitro toxicology play in drug development?

A

In vitro toxicology provides early indications of potential toxic effects, allowing researchers to terminate development programs for compounds that show significant toxicity before extensive investment.

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7
Q

What is the significance of the 5 Rs framework in lead optimization?

A

The 5 Rs framework guides the lead optimization process by focusing on the right target, the right tissue, the right time, the right route, and the right dose, ensuring a more systematic and effective approach to drug development.

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8
Q

What is meant by “target occupancy” in the context of lead optimization?

A

Target occupancy measures the extent to which a drug binds to its intended target in tissue or animals, providing insight into the drug’s potential effectiveness.

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9
Q

Why is it important to use both in vitro and in vivo studies during lead optimization?

A

Using both in vitro and in vivo studies allows for a comprehensive assessment of a compound’s pharmacodynamics, pharmacokinetics, and safety, ensuring a well-rounded evaluation before proceeding to human trials.

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10
Q

What happened during the Thalidomide disaster, and what lesson did it teach about drug safety?

A

The Thalidomide disaster occurred when the drug was prescribed to pregnant women for nausea, leading to severe birth defects. This highlighted the critical importance of rigorous toxicology testing to ensure drug safety before human use.

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11
Q

What is the importance of medicinal chemistry in lead optimization?

A

Medicinal chemistry is crucial in lead optimization as it involves designing and synthesizing new chemical compounds that improve the properties of lead candidates, enhancing their efficacy and safety profiles.

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12
Q

What is the significance of using a screening cascade in lead optimization?

A

A screening cascade involves a series of in vitro assays that provide information on a compound’s potency, selectivity, solubility, and stability, allowing researchers to make informed decisions about which compounds to advance.

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13
Q

How can pharmacodynamics influence lead optimization?

A

Pharmacodynamics examines how a drug affects the body, helping to identify the mechanisms of action and the therapeutic effects, which are critical for optimizing the efficacy of lead compounds.

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14
Q

What are some common reasons why drug development fails during lead optimization?

A

Drug development may fail due to insufficient efficacy, unacceptable toxicity, poor pharmacokinetic properties, or challenges in formulation and delivery.

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15
Q

What role do animal models play in assessing safety during lead optimization?

A

Animal models are used to evaluate the pharmacokinetics, pharmacodynamics, and overall safety profile of lead compounds, providing critical data on how these compounds behave in a living organism.

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16
Q

How does the concept of “structure-activity relationship” (SAR) apply to lead optimization?

A

SAR studies involve analysing how changes in a compound’s chemical structure affect its biological activity, guiding chemists in modifying lead compounds to enhance their therapeutic effects.

17
Q

What factors must be considered when designing a lead compound for optimal absorption?

A

actors include the compound’s solubility, permeability, stability in the gastrointestinal tract, and the presence of functional groups that may enhance absorption.

18
Q

What is the role of formulation in lead optimization?

A

Formulation involves creating the drug’s physical form (e.g., tablet, liquid) to ensure optimal delivery, stability, and release characteristics, impacting absorption and overall efficacy.

19
Q

How does the therapeutic window relate to lead optimization?

A

The therapeutic window is the range between the minimum effective dose and the minimum toxic dose. Optimizing a compound to have a wider therapeutic window increases its safety and efficacy for patients.

20
Q

What ethical considerations must be addressed during lead optimization, especially regarding animal testing?

A

Ethical considerations include ensuring that animal testing is necessary and justifiable, minimizing animal suffering, using the fewest animals possible, and adhering to regulations and guidelines for humane treatment.