Drug-Like Properties

Concepts, Structure Design and Methods from ADME to Toxicity Optimization

Li Di, Edward H Kerns

• Publisher: Academic Press
• Year: 2015
• ISBN:
  9780128013229
• Edition: 2
• Topic: Medizin
• Subtopic: Pharmakologie

Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, only a fraction have sufficient ADME (absorption, distribution, metabolism, elimination) properties, and acceptable toxicology properties, to become a drug product that will successfully complete human Phase I clinical trials. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization, Second Edition, provides scientists and students the background and tools to understand, discover, and develop optimal clinical candidates. This valuable resource explores physiochemical properties, including solubility and permeability, before exploring how compounds are absorbed, distributed, and metabolized safely and stably. Review chapters provide context and underscore the importance of key concepts such as pharmacokinetics, toxicity, the blood-brain barrier, diagnosing drug limitations, prodrugs, and formulation. Building on those foundations, this thoroughly updated revision covers a wide variety of current methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties for process and product improvement. From conducting key assays for interpretation and structural analysis, the reader learns to implement modification methods and improve each ADME property.

Through valuable case studies, structure-property relationship descriptions, and structure modification strategies, Drug-Like Properties, Second Edition, offers tools and methods for ADME/Tox scientists through all aspects of drug research, discovery, design, development, and optimization.

• Provides a comprehensive and valuable working handbook for scientists and students in medicinal chemistry
• Includes expanded coverage of pharmacokinetics fundamentals and effects
• Contains updates throughout, including the authors' recent work in the importance of solubility in drug development; new and currently used property methods, with a reduction of seldom-used methods; and exploration of computational modeling methods

Chapter 1

Introduction

Abstract

Drug discovery scientists are responsible for optimizing pharmacokinetics (PK) and safety of clinical candidates. This is done by focusing on drug properties, which are key elements that determine the PK and safety. The effort to optimize the PK and safety started with defining the physicochemical property ranges associated with drug-like PK and safety, and it has advanced to multiparameter optimization, pharmacokinetic/pharmacodynamic (PK/PD) modeling and physiologically based PK. This book discusses key drug properties and their fundamentals, effects, structure-activity relationships (SAR), structure modification approaches and assays, to assist drug discovery scientists.

Keywords

Drug-like

Properties

Chemical structure

Pharmacokinetics

Safety

SAR

Optimization

Target exposure

1.1 Drug-like Properties in Drug Discovery

Drug properties comprise the structural, physicochemical, biochemical, pharmacokinetic (PK), and toxicity characteristics of a compound. Certain values of drug properties are more advantageous for discovering new drugs. This concept advanced over many years. A key article that discussed advantageous property values commented:

“Drug-like is defined as those compounds that have sufficiently acceptable ADME properties and sufficiently acceptable toxicity properties to survive through the completion of human Phase I clinical trials.” [1]

ADME is absorption, distribution, metabolism, and excretion, the processes that determine PK. Phase I clinical trials measure human safety and PK. Thus, “drug-like properties” constitute a property profile that is consistent with the drug properties of most commercial drugs.

Drug properties were traditionally a focus of drug development. However, in the 1990s the responsibility of optimizing the drug properties of clinical candidates was given to drug discovery scientists. It has been commented:

“…drug-like properties are … intrinsic properties of the molecules and it is the responsibility of the medicinal chemists to optimize not only the pharmacological properties but also the drug-like properties of these molecules” [2]

Drug properties are an integral part of drug discovery. In the early phase of drug discovery, drug properties are used to select the “hits” that are suitable starting points for research on a new clinical candidate. They serve to focus drug discovery efforts into chemical space that has a higher probability of PK and safety success. Later in drug discovery, they have major influences on understanding structure-property relationships (SPR), guiding structure modifications for property optimization, diagnosing the causes of inadequate PK and toxicity, optimizing and interpreting bioassays, and building prospective models of human PK and its relationship to pharmacodynamics (PD). Medicinal chemists optimize the drug properties of leads in parallel with optimizing efficacy, selectivity, and novelty. This is accomplished by iteratively modifying the structure and measuring the properties of the new compound.

As drug discovery scientists extend the science of PK and toxicity, understanding about drug properties and their complex influence on drug candidates expands. The early focus on lipophilicity, molecular weight, and hydrogen bonding has expanded to complexities of properties, including solubility, permeability, metabolic enzymes, and transporters. The early concept of drug-like property ranges has advanced to multiparameter optimization approaches [3], pharmacokinetic/pharmacodynamic (PK/PD) modeling [4], and physiologically based PK (PBPK) [5]. This mirrors the increasing complexity and sophistication of all aspects of drug discovery, when scientists pursue multiple lines of investigation involving diverse disciplines. The focus is on integration of these disciplines through complex simultaneous studies to optimize and select new clinical candidates with a balance of efficacy, selectivity, PK, and safety [6].

One example of the fundamental role of PK and safety in drug discovery is the concept of “three pillars of survival” of drug candidates through Phase II [7]. The pillars are

“… the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity …”

Drug properties focus on the first pillar, exposure of the drug at the site of action. Thus, the field has advanced from general characteristics of drugs that succeed to detailed study of the complex physicochemistry and biochemistry that affect human PK and safety and effectively model human clinical outcomes.

1.2 Purpose of This Book

The various drug properties, terminology, and assays can be overwhelming to drug discovery scientists and students without sufficient introduction. Some texts on drug properties are daunting because they are written from the perspective of experts in pharmaceutics or drug metabolism/PK and contain detail and mathematical equations that are not easy to understand for drug discovery scientists. This book is a practical guide for medicinal chemists, biologists, pharmacologists, and students. It provides background material and real-world, practical examples for practicing drug discovery scientists who need to plan experiments, make sense of complex data, and arrive at informed decisions.

This book also provides tools for working with drug properties. First, the interactions of drug molecules with the in vivo environments they encounter after administration are described, in order to understand why properties limit drug exposure to the therapeutic target. Next, key drug properties are explored (Figure 1.1) in terms of

Figure 1.1 This book equips discovery scientists and students with a practical understanding of property fundamentals, property effects, and structure-property relationships that can be applied to improving lead series and biological activity. Literature examples of structure modification strategies to improve properties are described for chemists to apply to current projects. Information on property assays provides understanding of the available methods and reliable interpretation of the data.

(1) fundamentals of each property;

(2) effects of each property on PK, safety, and biological experiments;

(3) SPR case studies, to see how structure affects properties;

(4) structure modification strategies, to guide property optimization;

(5) strategies for using the properties to achieve a quality clinical candidate;

(6) effects of properties on in vitro and in vivo biological measurements;

(7) description of property methods, for accurate measurement and application of the data.

These equip drug discovery scientists for increased effectiveness in lead selection, lead optimization, and the enhancement of drug discovery biology and pharmacology assays.

Property-related concepts are described with a minimum of math and emphasis on practical application. Specific property applications in diagnosing poor PK, designing prodrugs, and formulation for in vivo dosing are also discussed.

A scheme for the workflow of this book is shown in Figure 1.1. Drug discovery has diverse elements that must be delicately integrated and balanced. Drug properties are important characteristics that help to achieve a quality clinical candidate.

Problems

(1) Define the term “drug-like”.

(2) What are two major lead optimization areas in drug discovery?

(3) How can understanding compound properties assist drug discovery biologists?

(4) Compound properties can affect which of the following: (a) pharmacokinetics, (b) bioavailability, (c) IC₅₀, (d) safety?

References

[1] Lipinsk...