Small Molecule Development & Molecular Properties

Orally Delivered Drugs

• Most Common Delivery Method:

  • Orally delivered drugs are the most frequent mode of administration for medication.

  • Their popularity arises from several factors:

  • Simplicity of use makes them easily accessible.

  • They are widely understood by the general population.

• Physical Properties Required:

  • Stability during storage and within the gastrointestinal (GI) tract, which includes:

  • Resistance to the acidic environment of the stomach and the action of proteases.

  • Sufficient solubility to ensure absorption.

  • Ability to be absorbed through the GI tract to enter systemic circulation.

  • Adequate residence time, meaning they should resist rapid metabolism (e.g., by the liver).

Target Product Profile (TPP)

• Definition:

  • TPP is a document that outlines the desired attributes of a new drug. It guides development based on the nature of the disease being treated and the characteristics of the target population.

• Purpose:

  • Assembles desired target properties to create a structured development plan.

  • Prepared early in the drug development process.

  • Includes both minimum acceptable and ideal values for various metrics.

TPP Example

• Variables in TPP:

  • Indications, products, target populations, target countries, clinical efficacy, microbiologic efficacy, safety/drug-drug interactions, formulations and dosage.

BPS2022 - Section 4: Small Molecule Development & Molecular Properties

Orally Delivered Drugs

• Most Common Delivery Method:

  • Orally delivered drugs are the most frequent mode of administration for medication.

  • Their popularity arises from several factors:

  • Simplicity of use makes them easily accessible.

  • They are widely understood by the general population.

• Physical Properties Required:

  • Stability during storage and within the gastrointestinal (GI) tract, which includes:

  • Resistance to the acidic environment of the stomach and the action of proteases.

  • Sufficient solubility to ensure absorption.

  • Ability to be absorbed through the GI tract to enter systemic circulation.

  • Adequate residence time, meaning they should resist rapid metabolism (e.g., by the liver).

Target Product Profile (TPP)

• Definition:

  • TPP is a document that outlines the desired attributes of a new drug. It guides development based on the nature of the disease being treated and the characteristics of the target population.

• Purpose:

  • Assembles desired target properties to create a structured development plan.

  • Prepared early in the drug development process.

  • Includes both minimum acceptable and ideal values for various metrics.

TPP Example

Small Molecule Optimization

• Drug Development as a Multi-Parameter Optimization:

  • Focuses on variables including:

  • Increased affinity/activity.

  • Reduced off-target binding (i.e., avoidance of unintended interactions).

  • Decreased metabolism.

  • Minimization of unwanted clearance rates.

  • Reduction of toxicity.

  • Enhancement of solubility (generally a target in most cases).

• Dependence on Molecular Structure:

  • Molecular properties change throughout the stages of development from hit to candidate.

Druglikeness

• Definition:

  • Druglikeness is the concept that outlines desirable properties of a small molecule drug.

• Evaluation:

  • Measures of druglikeness are assessed during development to ensure molecular properties are appropriate for drug candidates.

• Lipinski's Rule of 5:

  • A key example of a benchmark for assessing druglikeness, expressed as:

  • logP < 5

  • nHBD < 5 (number of hydrogen bond donors < 5)

  • n(O+N) < 10 (number of oxygen and nitrogen atoms < 10)

  • Polar surface area (PSA) < 150 \mathring{\text{A}}^2 (for oral bioavailability) or < 90 \mathring{\text{A}}^2 (for blood-brain barrier penetration).

• Lipophilic Efficiency (LipE):

  • Another important criterion in evaluating druglikeness.

• Note:

  • These druglikeness measures serve as essential development tools specifically designed for the optimization of oral drugs.

Property Changes During Development

• Example - Eprosartan (Angiotensin II Antagonist):

  • Used for hypertension treatment.

  • Changes during development included:

  • Major improvement in activity indicated by decreased IC50 values.

  • Increased hydrophobicity (initially increased, then decreased).

  • Molecular weight increased.

  • Chemical complexity also increased.

  • Implications:

  • Increased size and hydrophobicity often correlate with poor solubility, absorption, and increased off-target activities (toxicity).

• Graphical Example:

  • Transition from initial lead to final drug:

  • Initial lead:

    • IC50: 12 \muM, MW: 341, clogP: 3.08

  • Final drug (Eprosartan):

    • IC50: 0.08 \muM, MW: 424, clogP: 4.5

Why Do Molecular Properties Change?

• Initial Hits:

  • Starting molecules (initial hits) often exhibit lower activity, lack selectivity, and possess poor solubility/permeability.

• Interaction Importance:

  • Potency is heavily reliant on various interactions between the drug and its target receptor, including:

  • Hydrogen bonds

  • Ionic bonds

  • Van der Waals (vdW) interactions

  • Hydrophobic interactions

• Structure Development Trend:

  • During development, there is a tendency to add functional groups, logically leading to an increase in size, complexity, and hydrophobicity.

Effect of logD on Small Molecule Properties

• Definition of logD:

  • Represents lipophilicity and its impact on drug properties.

• Optimization Significance:

  • Managing and often reducing lipophilicity is a common focus in drug development processes.

Properties Related to Drug Development

• Activity Considerations:

  • Efficacy against various strains of Hepatitis C.

  • Metabolic actions by cytochrome P450 enzymes.

  • Membrane permeability.

  • Off-target binding, particularly concerning the HERG ion channel.

  • Molecular weight considerations (size).

  • LogD (lipophilicity) evaluations.

  • Solubility assessments.

Optimization of Anti-Hepatitis (NS4b) Compounds

• Context:

  • NS4b is a protein critical for the replication of the Hepatitis C virus.

• Synthesis and Properties:

  • Total compounds synthesized and their divergence from desired properties are important metrics in optimizing compounds.

• PEC50 Formula:

  • PEC50 = -log(effective concentration) = 1 - 10 nM.

Key Questions for Review

1. What is a TPP? Why is it important for a drug development program?

A TPP (Target Product Profile) is a strategic document that outlines the desired characteristics of a final drug product, including its indication, dosage form, route of administration, efficacy, safety, and target patient population.

It acts as a blueprint for development, guiding decision-making across discovery, preclinical, and clinical stages. The TPP helps teams stay focused on clinical and regulatory goals, ensuring that scientific efforts align with the intended therapeutic use and market needs.

It is important because it:

• Provides a clear vision of the product’s purpose and performance goals.

• Facilitates communication between multidisciplinary teams (scientists, clinicians, regulatory experts).

• Ensures regulatory alignment, since agencies like the FDA use the TPP format to evaluate development strategy.

• Helps manage resources and timelines efficiently.

2. What physical drug features influence small molecule lipophilicity?

Lipophilicity refers to a compound’s affinity for lipid (fat) environments over aqueous ones. For small molecules, key structural and physical features influencing lipophilicity include:

• Number of nonpolar (hydrocarbon) groups such as alkyl chains or aromatic rings (increase lipophilicity).

• Presence of polar functional groups like hydroxyl (-OH), amine (-NH₂), or carboxyl (-COOH) (decrease lipophilicity).

• Molecular size and shape, as larger and more compact molecules tend to be more lipophilic.

• Hydrogen bonding capacity, since molecules capable of forming hydrogen bonds with water are less lipophilic.

• Degree of ionization (pKa) — ionized species are more hydrophilic, while neutral forms are more lipophilic.

3. Why is compound lipophilicity considered important in drug development programs?

Lipophilicity is a critical determinant of a drug’s absorption, distribution, metabolism, and excretion (ADME) properties.

Why it matters:

• Absorption: Moderately lipophilic drugs cross biological membranes more easily, improving oral bioavailability.

• Distribution: Highly lipophilic drugs may accumulate in fatty tissues or cross the blood–brain barrier.

• Metabolism: Lipophilic compounds often undergo faster metabolism by liver enzymes, affecting half-life.

• Toxicity: Excessive lipophilicity can lead to off-target effects or poor solubility, increasing safety risks.

Factors affecting lipophilicity:

• Molecular structure (functional groups, polarity, size).

• Ionization state at physiological pH.

• Solvent and assay conditions used to measure it.

An optimal balance between lipophilicity and hydrophilicity is therefore essential for achieving good pharmacokinetics and safety.

4. How do molecular structures typically change as a drug program progresses from hit to clinical candidate?

As a drug program evolves from a hit compound (initial active molecule) to a clinical candidate (optimized molecule ready for trials), the structure is refined through medicinal chemistry optimization to improve potency, selectivity, and drug-like properties.

Typical changes include:

• Addition or removal of functional groups to improve solubility, potency, or metabolic stability.

• Optimization of lipophilicity to balance membrane permeability with solubility.

• Reduction of molecular weight or polarity for better oral absorption.

• Introduction of stereochemistry or rigid scaffolds to enhance receptor binding and selectivity.

• Blocking metabolic “soft spots” (sites prone to rapid degradation) to increase half-life.

In summary, molecular structures usually become more refined, potent, selective, and pharmacokinetically balanced as they move toward becoming clinical candidates.