4.5 Physicochemical properties

Physicochemical properties play a crucial role in drug design and development. These properties determine how a drug interacts with the body, affecting its absorption, distribution, metabolism, and excretion. Understanding these properties helps medicinal chemists create effective and safe medications.

Key properties include lipophilicity, solubility, ionization, and permeability. These factors influence how well a drug is absorbed, distributed throughout the body, and eliminated. By optimizing these properties, scientists can improve a drug's effectiveness and minimize potential side effects.

Properties affecting drug absorption

• Absorption refers to the process by which a drug moves from the site of administration into the bloodstream
• The physicochemical properties of a drug play a crucial role in determining its absorption characteristics
• Understanding these properties helps medicinal chemists design drugs with optimal absorption profiles

Lipophilicity vs hydrophilicity

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• Lipophilicity refers to a drug's affinity for lipids or fats, while hydrophilicity refers to its affinity for water
• Highly lipophilic drugs tend to cross biological membranes more easily, as cell membranes are composed of lipid bilayers
• However, extremely lipophilic drugs may have poor solubility in aqueous environments, limiting their absorption
• Hydrophilic drugs are more soluble in water but may struggle to pass through lipid-rich cell membranes

Solubility in biological fluids

• Solubility is the maximum amount of a drug that can dissolve in a given volume of solvent (e.g., water or gastrointestinal fluids)
• Drugs must be soluble in the aqueous environment of the gastrointestinal tract to be absorbed
• Poorly soluble drugs may precipitate in the gut, reducing their bioavailability
• Strategies to improve solubility include salt formation, prodrugs, and formulation techniques (e.g., micronization, solid dispersions)

Ionization of drugs

• Many drugs are weak acids or bases that can exist in ionized or unionized forms depending on the pH of their environment
• The ionization state of a drug affects its solubility, permeability, and absorption
• Unionized forms of drugs typically have higher permeability across cell membranes
• The Henderson-Hasselbalch equation relates pH, pKa, and the ratio of ionized to unionized drug: $pH = pKa + log([A-]/[HA])$

Partition coefficient

• The partition coefficient (log P) is a measure of a drug's lipophilicity, defined as the ratio of its concentration in an organic solvent (e.g., octanol) to its concentration in water at equilibrium
• Drugs with higher log P values are more lipophilic and generally have better membrane permeability
• However, extremely high log P values can lead to poor solubility and increased metabolic liability
• The optimal log P range for oral drugs is typically between 1 and 5

Drug permeability

• Permeability refers to a drug's ability to cross biological membranes, such as the intestinal epithelium or the blood-brain barrier
• Factors affecting permeability include lipophilicity, molecular size, charge, and the presence of transporters
• Passive diffusion is the primary mechanism for most drugs, favoring small, lipophilic molecules
• Active transport and facilitated diffusion can also contribute to drug permeability, mediated by specific transporters (e.g., P-glycoprotein)

Properties affecting drug distribution

• Distribution describes the process by which a drug moves from the bloodstream into various tissues and organs
• The extent and pattern of drug distribution depend on its physicochemical properties and its interactions with blood components and tissue structures

Plasma protein binding

• Many drugs bind reversibly to plasma proteins, such as albumin and alpha-1-acid glycoprotein
• Protein binding can affect a drug's distribution, as only the unbound (free) fraction is available to diffuse into tissues
• High protein binding can limit a drug's volume of distribution and reduce its clearance
• However, it can also prolong a drug's half-life and provide a reservoir for sustained release

Tissue binding

• Drugs may bind specifically or non-specifically to tissue components, such as proteins, lipids, or nucleic acids
• Tissue binding can lead to drug accumulation in certain organs (e.g., liver, kidneys) or in fatty tissues
• Extensive tissue binding may result in a large volume of distribution and a prolonged elimination half-life
• Tissue binding can also contribute to drug toxicity if the bound drug disrupts normal cellular functions

Blood-brain barrier penetration

• The blood-brain barrier (BBB) is a selective barrier that restricts the entry of substances from the bloodstream into the central nervous system (CNS)
• To cross the BBB, drugs must be lipophilic, have a low molecular weight (< 500 Da), and not be strongly bound to plasma proteins
• Drugs targeting CNS disorders (e.g., antidepressants, antipsychotics) must be designed to penetrate the BBB effectively
• Conversely, drugs intended for peripheral targets should minimize BBB penetration to avoid central side effects

Properties affecting drug metabolism

• Metabolism refers to the biochemical modification of drugs by enzymes, primarily in the liver
• The metabolic fate of a drug is determined by its chemical structure and its interactions with metabolic enzymes

Metabolic stability

• Metabolic stability is a measure of a drug's resistance to biotransformation by metabolic enzymes
• Drugs with high metabolic stability have a longer duration of action and require less frequent dosing
• However, metabolically stable drugs may accumulate in the body, leading to toxicity
• Balancing metabolic stability with clearance is crucial for optimizing drug exposure and safety

Cytochrome P450 interactions

• Cytochrome P450 (CYP) enzymes are a superfamily of heme-containing proteins responsible for the metabolism of many drugs
• CYP enzymes can be inhibited or induced by certain drugs, leading to drug-drug interactions
• CYP inhibition can increase the exposure and toxicity of substrate drugs, while CYP induction can decrease their efficacy
• Medicinal chemists aim to minimize CYP interactions by modifying drug structures or selecting compounds with favorable CYP profiles

Phase I vs Phase II metabolism

• Drug metabolism is divided into two phases: Phase I (functionalization) and Phase II (conjugation)
• Phase I reactions introduce or expose functional groups (e.g., hydroxylation, oxidation) and are primarily mediated by CYP enzymes
• Phase II reactions attach hydrophilic moieties (e.g., glucuronic acid, sulfate) to the drug or its Phase I metabolites, increasing their water solubility and facilitating excretion
• The balance between Phase I and Phase II metabolism can influence a drug's bioavailability, half-life, and toxicity

Prodrugs and active metabolites

• Prodrugs are inactive compounds that are metabolically converted into active drugs within the body
• Prodrug strategies can be used to improve solubility, permeability, or stability of the parent drug
• Examples of prodrugs include ester derivatives (e.g., aspirin, oseltamivir) and phosphate esters (e.g., cyclophosphamide)
• Some drugs are metabolized into active compounds that contribute to their pharmacological effects (e.g., codeine to morphine, tamoxifen to endoxifen)

Properties affecting drug excretion

• Excretion is the process by which drugs and their metabolites are eliminated from the body
• The primary routes of drug excretion are renal (via urine) and biliary (via feces), although other minor routes (e.g., sweat, saliva) may also contribute

Renal clearance

• Renal clearance is the volume of blood that is completely cleared of a drug by the kidneys per unit time
• Drugs are filtered, secreted, and reabsorbed in the nephron, the functional unit of the kidney
• Factors affecting renal clearance include glomerular filtration rate, tubular secretion, and tubular reabsorption
• Drugs with high renal clearance are rapidly eliminated from the body, while those with low renal clearance may accumulate and cause toxicity in patients with impaired kidney function

Biliary excretion

• Biliary excretion is the process by which drugs and their metabolites are eliminated from the body via the bile into the feces
• Drugs are actively transported from hepatocytes into the bile canaliculi by various transporters (e.g., P-glycoprotein, BCRP)
• Factors affecting biliary excretion include molecular weight, polarity, and transporter affinity
• Drugs with high biliary excretion may undergo enterohepatic recirculation, where they are reabsorbed from the intestine and returned to the liver, prolonging their half-life

Half-life and elimination rate

• The elimination half-life (t1/2) is the time required for the plasma concentration of a drug to decrease by 50% during the elimination phase
• The elimination rate constant (ke) is the fraction of a drug eliminated from the body per unit time and is related to the half-life by the equation: $t_{1/2} = \frac{ln(2)}{k_e}$
• Drugs with short half-lives require frequent dosing to maintain therapeutic concentrations, while those with long half-lives can be administered less frequently
• The elimination rate and half-life are influenced by the drug's clearance and volume of distribution

Structure-property relationships

• Structure-property relationships (SPRs) describe the connections between a drug's chemical structure and its physicochemical and pharmacokinetic properties
• Understanding SPRs allows medicinal chemists to rationally design drugs with desired properties and optimize lead compounds

Functional groups and properties

• Functional groups are specific arrangements of atoms within a molecule that confer characteristic properties
• Examples of functional groups include hydroxyl (-OH), amino (-NH2), carboxyl (-COOH), and ester (-COO-)
• The presence, absence, or modification of functional groups can significantly impact a drug's solubility, permeability, and metabolic stability
• For instance, adding a hydroxyl group can increase a drug's water solubility, while an ester group can improve its lipophilicity and permeability

Molecular size and shape

• The size and shape of a drug molecule can influence its absorption, distribution, and binding to targets
• Smaller molecules (molecular weight < 500 Da) generally have better oral bioavailability and can cross biological membranes more easily
• However, very small molecules (molecular weight < 200 Da) may have poor specificity and off-target effects
• The shape of a drug molecule, determined by its conformation and flexibility, can affect its interactions with receptors, enzymes, and transporters

Stereochemistry and drug properties

• Stereochemistry refers to the three-dimensional arrangement of atoms in a molecule
• Stereoisomers are compounds with the same molecular formula but different spatial arrangements (e.g., enantiomers, diastereomers)
• Stereochemistry can significantly impact a drug's pharmacokinetic and pharmacodynamic properties
• For example, the (S)-enantiomer of ibuprofen is more potent than the (R)-enantiomer, while the (R)-enantiomer of thalidomide is teratogenic

Quantitative structure-activity relationships (QSAR)

• QSAR is a computational approach that relates a drug's chemical structure to its biological activity using mathematical models
• QSAR models are built using a set of molecular descriptors (e.g., log P, molecular weight, topological indices) and statistical methods (e.g., multiple linear regression, partial least squares)
• QSAR can be used to predict the properties of new compounds, guide the optimization of lead compounds, and identify key structural features responsible for drug activity
• Examples of QSAR applications include the design of novel antibacterial agents and the prediction of ADME properties

Optimization of drug properties

• Drug optimization is the process of improving the properties of a lead compound to create a drug candidate suitable for clinical development
• The goal of optimization is to enhance the drug's efficacy, safety, and pharmacokinetic profile while maintaining its activity against the intended target

Strategies for improving solubility

• Improving solubility is crucial for ensuring adequate drug absorption and bioavailability
• Salt formation involves reacting the drug with an appropriate acid or base to create a more water-soluble ionic compound (e.g., sodium salt of ibuprofen)
• Prodrug approaches, such as ester or phosphate derivatives, can increase solubility by masking hydrophobic groups (e.g., fosamprenavir, a phosphate ester prodrug of amprenavir)
• Formulation techniques, such as micronization (reducing particle size), solid dispersions (dispersing the drug in a hydrophilic matrix), and cyclodextrin complexation, can enhance solubility without modifying the drug's chemical structure

Enhancing permeability and absorption

• Improving permeability and absorption is essential for drugs targeting intracellular or CNS receptors
• Increasing lipophilicity, for example, by adding non-polar groups or reducing hydrogen bond donors, can enhance passive diffusion across cell membranes
• Reducing molecular size or polar surface area can also improve permeability by facilitating passage through tight junctions or lipid bilayers
• Targeting specific transporters (e.g., amino acid or peptide transporters) can enable active uptake of drugs with suboptimal passive permeability

Reducing metabolic liability

• Minimizing metabolic liability is important for prolonging drug exposure and avoiding toxic metabolites
• Identifying and modifying metabolic "soft spots" (e.g., labile esters, oxidizable groups) can improve metabolic stability
• Replacing metabolically labile groups with more stable analogs (e.g., amides instead of esters, deuterium instead of hydrogen) can reduce CYP-mediated metabolism
• Designing compounds with reduced lipophilicity or increased polarity can decrease their affinity for metabolic enzymes and increase their excretion

Prolonging half-life and duration of action

• Extending a drug's half-life and duration of action can improve patient compliance and therapeutic outcomes
• Increasing plasma protein binding can create a reservoir of circulating drug, gradually releasing it over time
• Designing prodrugs with slow bioactivation rates can prolong the exposure to the active compound
• Incorporating structural features that reduce renal or biliary clearance (e.g., increasing molecular size, adding polar groups) can extend a drug's elimination half-life

Physicochemical profiling in drug discovery

• Physicochemical profiling involves the experimental and computational assessment of a drug's properties at various stages of the discovery process
• Profiling helps identify promising compounds, optimize lead structures, and predict in vivo performance

High-throughput screening assays

• High-throughput screening (HTS) assays are used to rapidly evaluate the properties of large compound libraries
• Solubility assays measure the concentration of a compound in aqueous buffer using UV/Vis spectroscopy or nephelometry
• Permeability assays assess a compound's ability to cross artificial membranes (e.g., PAMPA) or cell monolayers (e.g., Caco-2)
• Metabolic stability assays determine the rate of compound disappearance in the presence of liver microsomes or hepatocytes

In vitro ADME studies

• In vitro ADME (absorption, distribution, metabolism, excretion) studies provide more detailed information on a compound's pharmacokinetic properties
• Plasma protein binding is measured using equilibrium dialysis or ultrafiltration techniques
• Blood-brain barrier penetration is assessed using in vitro models such as MDCK or LLC-PK1 cell lines expressing efflux transporters
• CYP inhibition and induction studies evaluate the potential for drug-drug interactions using human liver microsomes or hepatocytes

In silico property prediction

• In silico methods use computational models to predict a compound's properties based on its chemical structure
• Quantitative structure-property relationship (QSPR) models correlate molecular descriptors with experimental property data using statistical techniques (e.g., multiple linear regression, artificial neural networks)
• Molecular docking simulations can predict a compound's binding affinity to targets such as enzymes or transporters
• Physiologically based pharmacokinetic (PBPK) models integrate in vitro and in silico data to predict a drug's absorption, distribution, metabolism, and excretion in humans

Druglikeness and lead optimization

• Druglikeness refers to the set of molecular properties that are consistent with orally active drugs
• Lipinski's Rule of Five is a widely used guideline for assessing druglikeness, based on molecular weight (≤ 500 Da), log P (≤ 5), hydrogen bond donors (≤ 5), and hydrogen bond acceptors (≤ 10)
• Other druglikeness filters include the Veber rules (rotatable bonds ≤ 10, polar surface area ≤ 140 Ų) and the Ghose filter (molecular weight between 160 and 480 Da, log P between -0.4 and 5.6)
• Lead optimization involves iterative cycles of synthesis, testing, and refinement to improve a compound's druglike properties while maintaining its potency and selectivity