Development of Enzyme Inhibitors as Drugs

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Development of Enzyme Inhibitors as Drugs 5 DevelopmentDrugs Inhibitors as of Enzyme H. John Smith and Claire SimonsCONTENTS5.1 Introduction 5.1.1 Basic Concepts 5.1.1.1 Substrate (Agonist) Accumulation or Preservation 5.1.1.2 Decrease in Metabolite Production5.2 Rational Selection of Suitable Target Enzyme and Inhibitor 5.2.1 Target Enzyme 5.2.2 Types of Inhibitor for Selected Target Enzyme 5.2.2.1 Reversible Inhibitors 5.2.2.2 Irreversible Inhibitors5.3 Selectivity and Toxicity5.4 Rational Approach to the Design of Enzyme Inhibitors 5.4.1 Lead Inhibitor Discovery 5.4.1.1 Modification of the Lead 5.4.2 Design from a Knowledge of the Catalytic Mechanism 5.4.2.1 Examples 5.4.3 Molecular Modeling 5.4.3.1 Crystal Structure of Enzyme or Enzyme–Inhibitor Complex Available 5.4.3.2 Prediction of 3-D Structure of Enzyme by Other Means5.5 Development of a Drug Candidate from the Bench to the Marketplace 5.5.1 Oral Absorption 5.5.2 Metabolism 5.5.2.1 Examples 5.5.3 Toxicity 5.5.3.1 Examples 5.5.4 Stereochemistry 5.5.4.1 Optical Stereoisomerism 5.5.5 Drug ResistanceFurther Reading5.6 Enzyme Inhibitor Examples for the Treatment of Breast Cancer L.W. Lawrence Woo 5.6.1 Introduction 5.6.2 Endocrine Therapy© 2005 by CRC Press 5.6.3 Aromatase 5.6.4 Inhibition of Aromatase as Endocrine Therapy 5.6.4.1 Nonsteroidal Aromatase Inhibitors (NSAIs) 5.6.4.2 Steroidal Aromatase Inhibitors 5.6.4.3 Computer-Aided Drug Design of Aromatase Inhibitors 5.6.5 Steroid Sulfatase 5.6.5.1 The Enzyme and Breast Cancer 5.6.6 Inhibition of Steroid Sulfatase as Endocrine Therapy 5.6.6.1 Steroidal STS Inhibitors 5.6.6.2 Nonsteroidal STS Inhibitors 5.6.6.3 Mechanism of Action for STS and STS Inhibitors 5.6.7 Future DirectionsAcknowledgmentFurther Reading5.7 Enzyme Inhibitor Examples for the Treatment of Prostate Tumor Samer Haidar and Rolf W. Hartmann 5.7.1 5a-Reductase and Androgen-Dependent Diseases 5.7.2 Inhibitors of 5a-Reductase 5.7.3 Prostate Cancer and CYP 17 5.7.4 Inhibitors of CYP 17Further Reading5.8 Thrombin Inhibitor Examples Torsten Steinmetzer 5.8.1 Introduction 5.8.2 First Electrophilic Substrate Analog Inhibitors 5.8.3 Nonelectrophilic Thrombin Inhibitors 5.8.3.1 H-DPhe-Pro-Agmatine Analogs 5.8.3.2 Secondary Amides of Sulfonylated Arginine 5.8.3.3 Benzamidine Derivatives of the NAPAP Type 5.8.3.4 Nonpeptidic Thrombin Inhibitors 5.8.4 Bivalent InhibitorsFurther Reading5.9 HIV-1 Protease Drug Development Examples Paul J. Ala and Chong-Hwan Chang 5.9.1 Introduction 5.9.2 Lead Discovery 5.9.2.1 Mechanism of Action 5.9.2.2 HIV-1 Protease Cleavage Sites 5.9.2.3 Structural Information 5.9.3 Lead Optimization 5.9.4 Drug ResistanceFurther Reading5.10 Metalloproteinase–Collagenase Inhibitor Examples Claudiu T. Supuran and Andrea Scozzafava 5.10.1 Introduction 5.10.2 Metalloproteinases 5.10.3 InhibitionReferences© 2005 by CRC Press5.1 INTRODUCTIONThe majority of drugs used clinically exert their action in one of two ways: (1) byinterfering with a component (agonist) in the body, preventing interaction with itssite of action (receptor), i.e., receptor antagonist, or (2) by interfering with an enzymenormally essential for the well-being of the body or involved in bacterial or parasiticor fungal growth causing disease and infectious states, where the removal of itsactivity by treatment is necessary, i.e., enzyme inhibitors. In recent years, the pro-portion of current drugs described as enzyme inhibitors has increased, and thischapter gives an account of the steps taken for designing and developing suchinhibitors — from identification of the target enzyme to be blocked in a particulardisease or infection to the marketplace. As has been described in previous chapters, enzymes catalyze the reactions oftheir substrates by initial formation of a complex (ES) between the enzyme (E) andthe substrate (S) at the active site of the enzyme. This complex then breaks down,either directly or through intermediary stages, to give the product (P) of the reactionwith regeneration of the enzyme (Equation 5.1 and Equation 5.2): E+S ES ækæÆ E + products cat enzyme-substrate (5.1) complex E+S ES æk 2 Æ æ E¢ + P1 æ 3 Æ E + P2 æ k (5.2) intermediatewhere kcat is the overall rate constant for decomposition of ES into products; k2 andk3 are the respective rate constants for formation and breakdown of the intermediateE¢ [i.e., kcat = k2k3/(k2 + k3)]. Chemical agents known as inhibitors modify the ability of an enzyme to catalyzethe reaction of its substrates, a term that is usually restricted to chemical agents,other modifiers of enzyme activity such as pH, ultraviolet light, high salt concen-trations, organic solvents, and heat being known as denaturizing agents.5.1.1 BASIC CONCEPTSThe body co ...