ADME and Drug Design Process Stages

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Questions and Answers

What are the 5 stages of the drug design and development process?

Identification and validation of disease-modifying targets, First studies of initial classes of compounds in animals, More in-depth pharmacology, Large-scale synthesis and formulation studies, Clinical trials

What are the two major strategies for disease-modifying target identification and validation?

Molecular approach and Systems approach

What are the three phases of clinical trials?

Phase I: safety, dosage, blood studies on healthy individuals; Phase II: efficacy, side effect studies on a limited group of patients; Phase III: efficacy, long-term and rare side effects studied with a large group of patients

When does patent protection usually expire in the drug development process?

After 17-25 years Signup and view all the answers

What does ADME stand for in the drug design and development process?

Absorption, distribution, metabolism, excretion Signup and view all the answers

What are some activities involved in the stage of large-scale synthesis and formulation studies?

Synthesis of most active compounds, Application for patent protection, Very large-scale synthesis Signup and view all the answers

What are the key aspects tested by a multitude of assays in drug development?

BBB: blood‐brain barrier, Cyp450: Cytochrome P450s, Pgp: P glycoprotein Signup and view all the answers

What are some important drug/lead characteristics apart from ADME?

Freedom from mutagenesis and teratogenicity, Chemical (shelf) stability, Solubility Signup and view all the answers

What is the most common method for optimizing drug leads through molecular modification?

Bioisosteric replacement ('molecular mimicry') Signup and view all the answers

How can bioisosteric replacement affect drug properties?

It can affect size, shape, electron distribution, solubility, pKa value, reactivity, and other properties. Signup and view all the answers

What is the purpose of classical bioisosteres?

To replace atoms or functional groups with similar valence to maintain biological properties. Signup and view all the answers

Give an example of a nonclassical bioisostere and its advantage.

Tetrazole, which is metabolically more stable than COOH and resists liver metabolism. Signup and view all the answers

What are some sources of drug leads mentioned in the text?

Substances derived from animal or plant sources, bacteria and fungi, endogenous compounds Signup and view all the answers

Why are many natural products highly potent and selective towards drug targets?

Due to their toxicity Signup and view all the answers

What are some examples of natural products that have been used to identify and characterize receptors?

Morphine, Strychnine, Nicotine, Muscarine Signup and view all the answers

Why have some biologically active natural products been replaced by other compounds?

Due to issues like toxicity, selectivity, and addictive properties Signup and view all the answers

What is the role of lead development and optimization in drug discovery?

Compounds must fulfill requirements including ADME, pharmacokinetics, and pharmacodynamics Signup and view all the answers

Define pharmacokinetics in the context of drug development.

Influence of the body on a drug as a function of time Signup and view all the answers

Define pharmacodynamics in the context of drug development.

Influence of the drug on the body as a function of time Signup and view all the answers

What does ADME stand for in drug development?

Absorption, distribution, metabolism, excretion Signup and view all the answers

Why must a drug be resistant to the action of liver enzymes in the body?

To avoid metabolism that may render the drug ineffective Signup and view all the answers

How are pharmacokinetics and pharmacodynamics related to a drug's chemical structure?

Both are influenced by the drug's chemical structure Signup and view all the answers

Study Notes

Drug Design and Development Process

The drug design and development process involves 5 stages: identification and validation of disease-modifying targets, selection of a promising approach, chemistry, pharmacology, and preclinical studies.

Identification and Validation of Disease-Modifying Targets

There are two major strategies for identifying disease-modifying targets: molecular approach and systems approach.
The molecular approach focuses on cells or cell components, using clinical samples and cell models.
The systems approach studies diseases in whole organisms.

Selection of a Promising Approach

A multidisciplinary research team is selected to develop a promising approach.
Budget decisions are made, and chemistry and pharmacology studies are conducted.

Preclinical Studies

Initial classes of compounds are studied in animals to determine potency, selectivity, and toxicity.
The most active compounds are synthesized, and their mode of action, efficacy, and toxicity are studied.
Large-scale synthesis and formulation studies are conducted, and patent protection is applied for.

Clinical Trials

Clinical trials involve three phases: Phase I (safety and dosage studies on healthy individuals), Phase II (efficacy and side effect studies on a limited group of patients), and Phase III (efficacy, long-term, and rare side effects studied on a large group of patients).
Regulatory review and marketing follow successful clinical trials.

Important Drug/Lead Characteristics

In addition to ADME (absorption, distribution, metabolism, excretion), a drug lead should have freedom from mutagenesis and teratogenicity, chemical stability, solubility, and satisfactory taste.
Medicinal chemists often modify lead compounds to achieve these characteristics.
Lead optimization involves varying substituents, extending or contracting the structure, ring closures, and simplifying or rigidifying the structure.

Bioisosteres

Bioisosteres are molecules with modified atoms or functional groups that retain therapeutic potential.
Bioisosteric replacement can affect molecular properties, such as size, shape, electron distribution, solubility, and reactivity, leading to changes in pharmacokinetic and dynamic properties.
Examples of classical bioisosteres include H to F, Cl, Br, I, OH, and CH3 replacements.

R&D Expenditures

Top pharmaceutical companies invest heavily in R&D, with some companies spending over 20% of their total sales on R&D.
Examples of companies and their R&D expenditures include Regeneron Pharmaceuticals, Vertex Pharmaceuticals, and Boehringer Ingelheim.

Discovery of Drug Candidates

Traditionally, drug discovery centered on natural products, such as those derived from animal or plant sources.
More recently, natural products from bacteria and fungi (e.g., penicillin) have been used for drug discovery.
Endogenous compounds and screening programs are also used to discover drug leads.

Natural Products in Target Identification

Many natural products are potent and selective towards drug targets due to their toxicity.
Examples include snake venom, clostridial toxins, and penicillins, which have been used to identify and characterize receptors.
Morphine, nicotine, and muscarine have been used to identify opioid, nicotinic, and muscarinic acetylcholine receptors.

Lead Development and Optimization

In addition to pharmacological activity, compounds must fulfill ADME requirements, including absorption, distribution, metabolism, and excretion.
Issues in lead development and optimization include surviving the harsh stomach environment, digestive enzymes, and liver enzymes.
Pharmacokinetics and pharmacodynamics are related to a drug's chemical structure and influence the body's response to the drug.

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Description

This quiz covers the 5 stages of the drug design and development process, including identification and validation of disease-modifying targets through molecular and systems approaches. It also touches on the selection of research teams, approaches, and budget decisions.