Pharmaceutical Chemistry. Volume 2: Drugs and Their Biological Targets

Description

This two volume book is an excellent introduction to this interdisciplinary area, lying on the interface between organic chemistry, biochemistry and medicine. The authors give a comprehensive overview of the field and outline the actual challenges in pharmaceutical science and industry. Volume 2 covers neurotransmitters, antihistamines, enzymatic inhibitors and nonsteroidal anti-inflammatory drugs. Provides a multidisciplinary approach to the field. Serves the needs of students and researchers. Includes case studies and practical examples aiming to help readers gain a broader understanding. Cover Half Title Also of Interest Pharmaceutical Chemistry. Volume 2: Drugs and Their Biological Targets Copyright Prologue Pharmaceutical chemistry Fundamental bibliography Complementary bibliography Contents 1. Acetylcholine 1.1 Goals 1.2 Nerve transmission through the synapse 1.3 Cholinergic nervous system: muscarinic and nicotinic receptors 1.4 Direct agonist drugs 1.5 Molecular modifications of AcC 1.5.1 Modifications in the ammonium moiety 1.5.2 Modifications of the ethylenic bridge 1.5.3 Modifications of the acyloxy group 1.6 Synthesis of methacholine and bethanechol 1.7 Muscarinic drugs derived from other models 1.8 Clinical uses of cholinergic agonists 1.8.1 Muscarinic agonists 1.8.2 Nicotinic agonists 1.9 Muscarinic antagonists. Clinical effects 1.9.1 Clinical uses 1.10 Muscarinic antagonists 1.10.1 Atropine 1.10.2 Hyoscine 1.11 Structural analogues based on atropine 1.12 Main anticholinergic drugs obtained by synthesis. Structure-activity relationships 1.13 M2 Antimuscarinics 1.14 Antagonist drugs on nicotinic receptors 1.14.1 Decamethonium and suxamethonium 1.14.2 Atracurium 1.15 Anticholinesterases and acetylcholinesterase 1.15.1 Effect of anticholinesterases 1.15.2 Acetylcholinesterase active center 1.15.2.1 Binding interactions at the active center 1.15.2.2 The mechanism of hydrolysis 1.15.3 Anticholinesterase drugs 1.15.3.1 Carbamates 1.15.3.2 Organophosphorus compounds 2. Noradrenaline 2.1 Goals 2.2 Introduction 2.3 Adrenergic synapses 2.4 Drugs that focus on the noradrenaline biosynthesis. False transmit 2.5 Drugs that affect the release of stored noradrenaline 2.6 Mechanism of action of the MAOs 2.7 Adrenergic indirect drugs 2.8 Catechol-O-methyltransferase inhibitors (COMT) 2.9 Direct adrenergic (postsynaptic agonists) drugs 2.10 Adrenergic β-blockers 2.10.1 Regioselective opening of epoxides in basic media 2.10.2 Regioselective opening of epoxides in acidic media 2.11 α−Adrenergic blockers 2.11.1 Competitive antagonists of the NA and A 2.11.2 Noncompetitive antagonists of NA, especially β-haloethylamines, capable of irreversibly alkylating the receptor 2.11.3 Benzodioxanes and other synthetic heterocycles. Imidazolines 3. Dopamine 3.1 Goals 3.2 Introduction: Antiparkinsonians related to the action or release of dopamine 3.2.1 Conformationally restricted analogues of dopamine 3.3 Direct agonists 3.4 MAO and COMT inhibitors 3.5 Drugs capable of causing the release of dopamine from the peripheral neural sites at the presynaptic level 3.6 Other dopaminergic agonists 3.7 Dopaminergic antagonists 3.7.1 Tricyclic neuroleptics: Phenothiazines and thioxanthenes 3.7.1.1 Synthesis of the tricyclic system 3.7.1.2 Pharmacophore of tricyclic neuroleptics 3.7.2 Butyrophenones and analogues 3.7.3 ortho-Methoxybenzamides (orthopramides) 4. Serotonin and reuptake inhibitors of biogenic amines 4.1 Goals 4.2 Introduction 4.3 Reuptake inhibitors: Tricyclic antidepressants 4.4 MAO inhibitors (MAOI) 4.5 Serotonin 4.6 Selective serotonin reuptake inhibitors (SSRIs) 4.7 Direct action on serotonergic receptors 4.7.1 5-HT1D Agonists. Antimigraine drugs 4.7.1.1 Sumatriptan and other triptans 4.7.2 5-HT1A Agonists 4.7.3 5-HT3 Antagonists 4.8 Summary 5. Amino acids as neurotransmitters 5.1 Goals 5.2 Introduction 5.3 Inhibitors of γ-aminobutyric acid (GABA) 5.4 Presynaptic modulators 5.5 Enzymic inhibitors that have pyridoxal phosphate as cofactor 5.6 Postsinaptic modulators 5.6.1 Benzodiazepines 5.6.1.1 Mechanism of the rearrangement reaction to 1,4-benzodiazepines 5.6.1.2 Mechanism of metabolic hydrolysis of chlordiazepoxide (Librium®, 1960) 5.6.1.3 Second-generation benzodiazepines [diazepam (Valium®)] 5.6.1.4 Structure-activity relationships 5.6.2 Fixation of steroids to GABAA 5.6.3 Other drugs related to benzodiazepines 5.6.4 Barbituric acids (or barbiturates) 6. Peptides as neurotransmitters: Hypnoanalgesics 6.1 Goals 6.2 Morphine 6.2.1 SARs 6.2.1.1 The phenolic group 6.2.1.2 Alcohol at 6-position 6.2.1.3 The 7-8 double bond 6.2.1.4 The N-methyl group 6.2.1.5 E-ring and the ethereal bridge 6.2.1.6 Stereochemistry 6.2.2 Development of morphine analogues: Strategies 6.2.2.1 Extension of the drug: addition of “extra” binding groups (Fig. 6.10) 6.2.2.2 Simplification or dissection of the drug 6.2.2.3 Increased rigidity 6.2.3 Multiple analgesic receptors 6.2.3.1 Mu receptor (μ) 6.2.3.2 Kappa receptor (κ) 6.2.3.3 Delta receptor (δ) 6.2.4 Agonists and antagonists 6.2.5 Enkephalins and endorphins 6.2.6 Enkephalin analogues 7. Histamine and antihistaminics 7.1 Goals 7.2 Histamine 7.2.1 H1 Antihistaminics: synthesis and SARs 7.2.2 Second-generation H1 antihistaminics 7.3 Cimetidine: Example of a rational approach in the design of a drug 7.3.1 Beginnings: ulcer therapy in 1964 7.3.2 Two histaminic receptors 7.3.3 Looking for a leader: histamine 7.4 Searching for a leader: Nα-Guanylhistamine 7.5 The theory of chelation 7.6 From a partial agonist to an antagonist: Development of burimamide 7.7 Development of methiamide 7.8 Cimetidine development 7.8.1 Cimetidine metabolism 7.8.2 Cimetidine synthesis 7.8.3 Conformational isomers of cimetidine 7.8.4 Desolvation 7.8.5 Development of the ketenaminal (or diaminonitroethylene) group 7.9 Variation of the imidazole ring and the cyanoguanidine moiety of cimetidine: ranitidine 7.10 Summary of cimetidine design 7.11 Comparison between H1 and H2 antagonists 8. Enzymatic inhibitors I 8.1 Goals 8.2 Introduction 8.3 Carbonic anhydrase (CA) inhibitors 8.4 Renin-angiotensin pathway 8.4.1 Angiotensin II antagonists. X-ray crystallographic studies 9. Enzimatic inhibitors II 9.1 Goals 9.2 Introduction 9.3 Classification of nonsteroidal anti-inflammatory drugs (NSAIDs) 9.3.1 Arylacetic acids or “fenacs” 9.3.2 Arylpropionic acids or “profens” 9.3.3 Naproxen 9.3.4 N-Arylanthranilic (fenamic) acids 9.3.5 Enols (oxicams) 9.3.6 COX-2 selective inhibitors: Coxibs 10. Design of drugs acting on transport through biological membranes 10.1 Goals 10.2 Design of drugs that act on transport through cell membranes 10.3 Voltage-gated sodium channels 10.3.1 Local anesthetics 10.4 Voltage-dependent calcium channels 10.4.1 Calcium channel blockers: Structural families 10.4.1.1 1,4-Dihydropyridines 10.4.1.2 Agents that act as activators of K+ 10.4.2 H+/K+-ATPase inhibitors: Antiulcer drugs 11. Enzymatic inhibition: Inhibitors of the biosinthesis of the cellular wall 11.1 Goals 11.2 Antibiotics 11.3 Penicillins 11.3.1 Structure of penicillins 11.3.2 Various penicillins 11.3.3 Properties of penicillin G 11.3.4 Structure-activity relationships of penicillins 11.3.5 Sensitivity of penicillin G to acids 11.3.5.1 Ring strain 11.3.5.2 The highly reactive carbonyl group of the β-lactam system 11.3.5.3 Influence of the acylic lateral chain (neighboring-group participation) 11.3.5.4 Facing the problem of acid sensitivity 11.3.6 Penicillins sensitive to β-lactamases 11.3.7 Facing the problem of β-lactamase sensitivity 11.3.8 Resistance to penicillins 11.3.8.1 Permeability barrier 11.3.8.2 High levels of the enzyme transpeptidase 11.3.8.3 Presence of β-lactamases 11.3.9 Addressing the narrow-spectrum problem 11.4 Cephalosporins 11.4.1 SARs of cephalosporin C 11.4.2 Cephalosporin C analogues by variation of the 7-acylamine side chain 11.4.3 Cephalosporin C analogues by variation of the 3-acetoxymethyl side chain 11.4.4 Synthesis of 3-methylated cephalosporins 11.4.5 Disclaimer 11.4.6 Summary of the properties of cephalosporins 11.5 Clavulanic acid (Beechams, 1976) 11.6 Mechanism of action of penicillins and cephalosporins 12. Enzymatic inhibition: Other antibacterial agents 12.1 Goals 12.2 Introduction 12.3 SARs 12.4 Sulfanilamide analogues 12.5 Applications of sulfonamides 12.6 Mechanism of action 12.7 Synthesis of sulfonamides 12.8 Examples of other antimetabolites 12.8.1 Trimethoprim 12.9 Antibacterial agents affecting protein synthesis 12.9.1 Rifamycins 12.9.2 Aminoglycosides 12.9.3 Tetracyclines 12.9.4 Chloramphenicol 12.9.5 Erythromycin 12.9.6 Aminoacridines 12.9.7 1,8-Naphthyridine and fluoroquinolones 13. Enzymatic inhibition: Inhibitors of biosinthesis of nitrogenated bases 13.1 Goals 13.2 Introduction 13.3 Nucleic acids 13.4 Thymidylate synthase inhibitors 13.4.1 Tetrahydrofolic acid 13.4.2 5-Fluorouracil (5-FU) 13.5 DHFR inhibitors 13.6 Tyrosine kinase inhibitors 13.6.1 Structure of tyrosine kinase receptors 13.6.2 Mechanisms of activation of the EGF receptor tyrosine kinase 13.6.3 Example of a kinase inhibitor for clinical use (gefitinib) 13.7 Antivirals 13.7.1 Antiviral inhibitors of DNA polymerases and other enzymes Index