The Organic Chemistry of Drug Design and Drug Action

by Silverman

• ISBN13: 9780126437324
• ISBN10: 0126437327
• Edition: 2nd
• Format: Hardcover
• Copyright: 2004-01-12
• Publisher: Elsevier Science

Summary

Standard medicinal texts are organized by classes of drugs with an emphasis on descriptions of their pharmacological effects. This book represents a new approach based on physical organic chemical principles and reaction mechanisms that rationalized drug action and allows the reader to extrapolate to many related classed of drug molecules.

Table of Contents

Preface to the First Edition	xv
Preface to the Second Edition	xvii
1 Introduction	1	(6)
1.1 Medicinal Chemistry Folklore	1	(1)
1.2 Discovery of New Drugs	2	(1)
1.3 General References	3	(1)
1.4 References	4	(3)
2 Drug Discovery, Design, and Development	7	(114)
2.1 Drug Discovery	8	(9)
2.1.A LA Drug Discovery without a Lead	9	(2)
A.1 Penicillins	9	(1)
A.2 Librium	10	(1)
2.1.B Lead Discovery	11	(6)
B.1 Random Screening	13	(1)
B.2 Nonrandom (or Targeted or Focused) Screening	14	(1)
B.3 Drug Metabolism Studies	14	(1)
B.4 Clinical Observations	15	(1)
B.5 Rational Approaches to Lead Discovery	16	(1)
2.2 Lead Modification: Drug Design and Development	17	(70)
2.2.A Identification of the Active Part: The Pharmacophore	17	(4)
2.2.B Functional Group Modification	21	(1)
2.2.C Structure-Activity Relationships	21	(3)
2.2.D Privileged Structures and Drug-Like Molecules	24	(1)
2.2.E Structure Modifications to Increase Potency and the Therapeutic Index	25	(26)
E.1 Homologation	26	(1)
E.2 Chain Branching	26	(2)
E.3 Ring-Chain Transformations	28	(1)
E.4 Bioisosterism	29	(5)
E.5 Combinatorial Chemistry	34	(10)
a. General Aspects	34	(2)
b. Split Synthesis: Peptide Libraries	36	(2)
c. Encoding Combinatorial Libraries	38	(3)
d. Nonpeptide Libraries	41	(3)
E.6 SAR by NMR/SAR by MS	44	(3)
E.7 Peptidomimetics	47	(4)
2.2.F Structure Modifications to Increase Oral Bioavailability	51	(15)
F.1 Electronic Effects: The Hammett Equation	51	(2)
F.2 Lipophilicity Effects	53	(9)
a. Importance of Lipophilicity	53	(2)
b. Measurement of Lipophilicities	55	(6)
c. Computerization of Log P Values	61	(1)
d. Membrane Lipophilicity	62	(1)
F.3 Effects of Ionization on Lipophilicity and Oral Bioavailability	62	(3)
F.4 Other Properties that Influence Oral Bioavailability and Ability to Cross the Blood-Brain Barrier	65	(1)
2.2.G Quantitative Structure-Activity Relationships	66	(12)
G.1 Historical	66	(1)
G.2 Steric Effects: The Taft Equation and Other Equations	67	(1)
G.3 Methods Used to Correlate Physicochemical Parameters with Biological Activity	68	(7)
a. Hansch Analysis: A Linear Multiple Regression Analysis	68	(2)
b. Free and Wilson or de novo Method	70	(1)
c. Enhancement Factor	71	(1)
d. Manual Stepwise Methods: Topliss Operational Schemes and Others	71	(2)
e. Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others	73	(2)
G.4 Computer-Based Methods of QSAR Related to Receptor Binding: 3D-QSAR	75	(3)
2.2.H Molecular Graphics-Based Drug Design	78	(8)
2.2.I Epilogue	86	(1)
2.3 General References	87	(13)
2.4 Problems	100	(5)
2.5 References	105	(16)
3 Receptors	121	(52)
3.1 Introduction	122	(1)
3.2 Drug-Receptor Interactions	123	(42)
3.2.A General Considerations	123	(1)
3.2.B Interactions (Forces) Involved in the Drug-Receptor Complex	124	(7)
B.1 Covalent Bonds	125	(1)
B.2 Ionic (or Electrostatic) Interactions	125	(1)
B.3 Ion-Dipole and Dipole-Dipole Interactions	125	(1)
B.4 Hydrogen Bonds	125	(2)
B.5 Charge-Transfer Complexes	127	(2)
B.6 Hydrophobic Interactions	129	(1)
B.7 Van der Waals or London Dispersion Forces	129	(1)
B.8 Conclusion	130	(1)
3.2.C Determination of Drug-Receptor Interactions	131	(6)
3.2.D Theories for Drug-Receptor Interactions	137	(5)
D.1 Occupancy Theory	137	(2)
D.2 Rate Theory	139	(1)
D.3 Induced-Fit Theory	139	(1)
D.4 Macromolecular Perturbation Theory	139	(1)
D.5 Activation-Aggregation Theory	140	(1)
D.6 The Two-State (Multistate) Model of Receptor Activation	141	(1)
3.2.E Topographical and Stereochemical Considerations	142	(16)
E.1 Spatial Arrangement of Atoms	142	(1)
E.2 Drug and Receptor Chirality	143	(8)
E.3 Geometric Isomers (Diastereomers)	151	(1)
E.4 Conformational Isomers	152	(6)
E.5 Ring Topology	158	(1)
3.2.F Ion Channel Blockers	158	(1)
3.2.G Case History of Rational Drug Design of a Receptor Antagonist: Cimetidine	159	(6)
3.3 General References	165	(1)
3.4 Problems	166	(2)
3.5 References	168	(5)
4 Enzymes	173	(54)
4.1 Enzymes as Catalysts	174	(5)
4.1.A What Are Enzymes?	174	(1)
4.1.B How Do Enzymes Work?	174	(5)
B.1 Specificity of Enzyme-Catalyzed Reactions	176	(2)
a. Binding Specificity	176	(1)
b. Reaction Specificity	177	(1)
B.2 Rate Acceleration	178	(1)
4.2 Mechanisms of Enzyme Catalysis	179	(9)
4.2.A Approximation	179	(2)
4.2.B Covalent Catalysis	181	(1)
4.2.C General Acid-Base Catalysis	182	(2)
4.2.D Electrostatic Catalysis	184	(1)
4.2.E Desolvation	185	(1)
4.2.F Strain or Distortion	185	(1)
4.2.G Example of the Mechanisms of Enzyme Catalysis	186	(2)
4.3 Coenzyme Catalysis	188	(28)
4.3.A Pyridoxal 5'-Phosphate (PLP)	188	(12)
A.1 Racemases	194	(1)
A.2 Decarboxylases	195	(1)
A.3 Aminotransferases (Formerly Transaminases)	195	(5)
A.4 PLP-Dependent ß-Elimination	200	(1)
4.3.B Tetrahydrofolate and Pyridine Nucleotides	200	(5)
4.3.C Flavin	205	(7)
C.1 Two-Electron (Carbanion) Mechanism	209	(1)
C.2 Carbanion Followed by Two One-Electron Transfers	209	(1)
C.3 One-Electron Mechanism	210	(1)
C.4 Hydride Mechanism	210	(2)
4.3.D Heme	212	(2)
4.3.E Adenosine Triphosphate and Coenzyme A	214	(2)
4.4 Enzyme Therapy	216	(1)
4.5 General References	217	(1)
4.6 Problems	218	(4)
4.7 References	222	(5)
5 Enzyme Inhibition and Inactivation	227	(96)
5.1 Why Inhibit an Enzyme?	229	(2)
5.2 Drug Resistance	231	(8)
52.A What Is Drug Resistance?	231	(1)
52.B Mechanisms of Drug Resistance	232	(7)
B.1 Altered Drug Uptake	232	(1)
B.2 Overproduction of the Target Enzyme	232	(1)
B.3 Altered Target Enzyme (or Site of Action)	232	(3)
B.4 Production of a Drug-Destroying Enzyme	235	(3)
B.5 Deletion of a Prodrug-Activating Enzyme	238	(1)
B.6 Overproduction of the Substrate for the Target Enzyme	239	(1)
B.7 New Pathway for Formation of the Product of the Target Enzyme	239	(1)
B.8 Efflux Pumps	239	(1)
5.3 Drug Synergism (Drug Combination)	239	(2)
5.3.A What Is Drug Synergism?	239	(1)
5.3.B Mechanisms of Drug Synergism	239	(2)
B.1 Inhibition of a Drug-Destroying Enzyme	239	(1)
B.2 Sequential Blocking	240	(1)
B.3 Inhibition of Enzymes in Different Metabolic Pathways	240	(1)
B.4 Efflux Pump Inhibitors	240	(1)
B.5 Use of Multiple Drugs for the Same Target	240	(1)
5.4 Reversible Enzyme Inhibitors	241	(33)
5.4.A Mechanism of Reversible Inhibition	241	(1)
5.4.B Selected Examples of Competitive Reversible Inhibitor Drugs	242	(16)
B.1 Simple Competitive Inhibition: Captopril, Enalapril, Lisinopril, and Other Antihypertensive Drugs	242	(12)
a. Humoral Mechanism for Hypertension	243	(1)
b. Lead Discovery	243	(1)
c. Lead Modification and Mechanism of Action	244	(6)
d. Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors	250	(4)
B.2 Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa Drugs)	254	(4)
a. Lead Discovery	254	(1)
b. Lead Modification	255	(1)
c. Mechanism of Action	255	(2)
d. Drug Resistance	257	(1)
e. Drug Synergism	257	(1)
5.4.C Transition State Analogs and Multisubstrate Analogs	258	(4)
C.1 Theoretical Basis	258	(1)
C.2 Transition State Analogs	259	(3)
a. Enalaprilat	259	(1)
b. Pentostatin	259	(3)
c. Multisubstrate Analogs	262	(1)
5.4.D Slow, Tight-Binding Inhibitors	262	(6)
D.1 Theoretical Basis	262	(1)
D.2 Enalaprilat	263	(1)
D.3 Lovastatin and Simvastatin, Antihypercholesterolemic Drugs	263	(4)
a. Cholesterol and Its Effects	263	(1)
b. Lead Discovery	263	(1)
c. Mechanism of Action	264	(1)
d. Lead Modification	265	(2)
D.4 Peptidyl Trifluoromethyl Ketone Inhibitors of Human Leukocyte Elastase	267	(1)
5.4.E Case History of Rational Drug Design of an Enzyme Inhibitor: Ritonavir	268	(6)
E.1 Lead Discovery	268	(1)
E.2 Lead Modification	269	(5)
5.5 Irreversible Enzyme Inhibitors	274	(28)
5.5.A Potential of Irreversible Inhibition	274	(1)
5.5.B Affinity Labeling Agents	275	(10)
B.1 Mechanism of Action	275	(2)
B.2 Selected Affinity Labeling Agents	277	(8)
a. Penicillins and Cephalosporins/Cephamycins	277	(3)
b. Aspirin	280	(5)
5.5.C Mechanism-Based Enzyme Inactivators	285	(39)
C.1 Theoretical Aspects	285	(1)
C.2 Potential Advantages in Drug Design Relative to Affinity Labeling Agents	286	(1)
C.3 Selected Examples of Mechanism-Based Enzyme Inactivators	287	(57)
a. Vigabatrin, an Anticonvulsant Drug	287	(3)
b. Eflornithine, an Antiprotozoal Drug and Beyond	290	(2)
c. Tranylcypromine, an Antidepressant Drug	292	(3)
d. Selegiline (L-Deprenyl), an Antiparkinsonian Drug	295	(3)
e. 5-Fluoro-2'-Deoxyuridylate, Floxuridine, and 5-Fluorouracil, Antitumor Drugs	298	(4)
5.6 General References	302	(1)
5.7 Problems	303	(4)
5.8 References	307	(16)
6 DNA-Interactive Agents	323	(82)
6.1 Introduction	324	(4)
6.1.A Basis for DNA-Interactive Drugs	324	(1)
6.1.B Toxicity of DNA-Interactive Drugs	325	(2)
6.1.C Combination Chemotherapy	327	(1)
6.1.D Drug Interactions	327	(1)
6.1.E Drug Resistance	327	(1)
6.2 DNA Structure and Properties	328	(14)
6.2.A Basis for the Structure of DNA	328	(4)
6.2.B Base Tautomerization	332	(2)
6.2.C DNA Shapes	334	(7)
6.2.D DNA Conformations	341	(1)
6.3 Classes of Drugs That Interact with DNA	342	(44)
6.3.A Reversible DNA Binders	344	(9)
A.1 External Electrostatic Binding	345	(1)
A.2 Groove Binding	345	(1)
A.3 Intercalation and Topoisomerase-Induced DNA Damage	346	(7)
a. Amsacrine, an Acridine Analog	349	(1)
b. Dactinomycin, the Parent Actinomycin Analog	350	(1)
c. Doxorubicin (Adriamycin) and Daunorubicin (Daunomycin), Anthracycline Antitumor Antibiotics	351	(1)
d. Bisintercalating Agents	352	(1)
6.3.B DNA Alkylators	353	(58)
B.1 Nitrogen Mustards	354	(4)
a. Lead Discovery	354	(1)
b. Chemistry of Alkylating Agents	354	(2)
c. Lead Modification	356	(2)
d. Drug Resistance	358	(1)
B.2 Ethylenimines	358	(1)
B.3 Methanesulfonates	358	(1)
B.4 (+)-CC-1065 and Duocarmycins	359	(2)
B.5 Metabolically Activated Alkylating Agents	361	(7)
a. Nitrosoureas	361	(2)
b. Triazene Antitumor Drugs	363	(1)
c. Mitomycin C	364	(2)
d. Leinamycin	366	(2)
6.3.C DNA Strand Breakers	368	(50)
C.1 Anthracycline Antitumor Antibiotics	369	(2)
C.2 Bleomycin	371	(6)
C.3 Tirapazamine	377	(1)
C.4 Enediyne Antitumor Antibiotics	378	(1)
a. Esperamicins and Calicheamicins	380	(1)
b. Dynemicin A	381	(1)
c. Neocarzinostatin (Zinostatin)	381	(5)
C.5 Sequence Specificity for DNA Strand Scission	386	(1)
6.4 Epilogue to Receptor-Interactive Agents	386	(1)
6.5 General References	386	(1)
6.6 Problems	387	(2)
6.7 References	389	(16)
7 Drug Metabolism	405	(92)
7.1 Introduction	406	(2)
7.2 Synthesis of Radioactive Compounds	408	(3)
7.3 Analytical Methods in Drug Metabolism	411	(4)
7.3.A Isolation	412	(1)
7.3.B Separation	412	(1)
7.3.C Identification	413	(1)
7.3.D Quantification	414	(1)
7.4 Pathways for Drug Deactivation and Elimination	415	(58)
7.4.A Introduction	415	(3)
7.4.B Phase I Transformations	418	(38)
B.1 Oxidative Reactions	418	(30)
a. Aromatic Hydroxylation	420	(7)
b. Alkene Epoxidation	427	(1)
c. Oxidations of Carbons Adjacent to sp2 Centers	428	(2)
d. Oxidation at Aliphatic and Alicyclic Carbon Atoms	430	(1)
e. Oxidations of Carbon-Nitrogen Systems	430	(13)
f. Oxidations of Carbon-Oxygen Systems	443	(1)
g. Oxidations of Carbon-Sulfur Systems	444	(2)
h. Other Oxidative Reactions	446	(1)
i. Alcohol and Aldehyde Oxidations	447	(1)
B.2 Reductive Reactions	448	(5)
a. Carbonyl Reduction	448	(2)
b. Nitro Reduction	450	(1)
c. Azo Reduction	451	(1)
d. Azido Reduction	452	(1)
e. Tertiary Amine Oxide Reduction	452	(1)
f. Reductive Dehalogenation	453	(1)
B.3 Carboxylation Reaction	453	(1)
B.4 Hydrolytic Reactions	454	(2)
7.4.C Phase II Transformations: Conjugation Reactions	456	(15)
C.1 Introduction	456	(1)
C.2 Glucuronic Acid Conjugation	456	(4)
C.3 Sulfate Conjugation	460	(2)
C.4 Amino Acid Conjugation	462	(2)
C.5 Glutathione Conjugation	464	(2)
C.6 Water Conjugation	466	(1)
C.7 Acetyl Conjugation	466	(2)
C.8 Fatty Acid and Cholesterol Conjugation	468	(1)
C.9 Methyl Conjugation	469	(2)
7.4.D Hard and Soft Drugs; Antedrugs	471	(2)
7.5 General References	473	(2)
7.6 Problems	475	(4)
7.7 References	479	(18)
8 Prodrugs and Drug Delivery Systems	497	(62)
8.1 Enzyme Activation of Drugs	498	(3)
8.1.A Utility of Prodrugs	498	(2)
A.1 Aqueous Solubility	499	(1)
A.2 Absorption and Distribution	499	(1)
A.3 Site Specificity	499	(1)
A.4 Instability	499	(1)
A.5 Prolonged Release	499	(1)
A.6 Toxicity	499	(1)
A.7 Poor Patient Acceptability	499	(1)
A.8 Formulation Problems	500	(1)
8.1.B Types of Prodrugs	500	(1)
8.2 Mechanisms of Drug Activation	501	(45)
8.2.A Carrier-Linked Prodrugs	501	(25)
A.1 Carrier Linkages for Various Functional Groups	501	(4)
a. Alcohols, Carboxylic Acids, and Related Groups	501	(2)
b. Amines	503	(1)
c. Sulfonamides	504	(1)
d. Carbonyl Compounds	505	(1)
A.2 Examples of Carrier-Linked Bipartate Prodrugs	505	(11)
a. Prodrugs for Increased Water Solubility	505	(2)
b. Prodrugs for Improved Absorption and Distribution	507	(1)
c. Prodrugs for Site Specificity	507	(5)
d. Prodrugs for Stability	512	(1)
e. Prodrugs for Slow and Prolonged Release	513	(1)
f. Prodrugs to Minimize Toxicity	514	(1)
g. Prodrugs to Encourage Patient Acceptance	514	(1)
h. Prodrugs to Eliminate Formulation Problems	515	(1)
A.3 Macromolecular Drug Carrier Systems	516	(4)
a. General Strategy	516	(1)
b. Synthetic Polymers	517	(1)
c. Poly (a-amino acids)	517	(2)
d. Other Macromolecular Supports	519	(1)
A.4 Tripartate Prodrugs	520	(5)
A.5 Mutual Prodrugs	525	(1)
8.2.B Bioprecursor Prodrugs	526	(20)
B.1 Origins	526	(1)
B.2 Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole	527	(1)
B.3 Hydrolytic Activation	528	(2)
B.4 Elimination Activation	530	(1)
B.5 Oxidative Activation	530	(7)
a. N- and O-Dealkylations	530	(1)
b. Oxidative Deamination	530	(2)
c. N-Oxidation	532	(3)
d. S-Oxidation	535	(1)
e. Aromatic Hydroxylation	536	(1)
f. Other Oxidations	536	(1)
B.6 Reductive Activation	537	(3)
a. Azo Reduction	537	(1)
b. Azido Reduction	538	(1)
c. Sulfoxide Reduction	538	(1)
d. Disulfide Reduction	538	(1)
e. Nitro Reduction	539	(1)
B.7 Nucleotide Activation	540	(1)
B.8 Phosphorylation Activation	541	(2)
B.9 Sulfation Activation	543	(1)
B.10 Decarboxylation Activation	544	(2)
8.3 General References	546	(1)
8.4 Problems	547	(2)
8.5 References	549	(10)
Appendix Answers to Chapter Problems	559	(34)
Index	593