Drug Discovery

INDEX

Downloaded by 80.82.77.83 on May 27, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ix001

A

Abortion 29 Abuse, drug 172 Acetylcholine 101,145 Acetylcholinesterase ( AChE ) . . . 148 structure of 150 Actinomycetes, antimicrobial activity of 34-5 Actinomycins 67 Action, drug 169 Activity growth-inhibitory 11 studies, structure124 Adrenal steroid research 17 /3-Adrenergic blocking drugs . . . . 92 Adrenergic systems 151 Advertising by drug companies . . 202 Affinity 82 Agents antiarrhythmic 92, 278 psychotherapeutic 166 Aldomet 90 Allopurinol 98,169 Amendments, drug law 181 Amendments to the Food, Drug, and Cosmetic Act 247 Aminoglycosides 49 6-Aminopenicillanic acid 58 Amphetamine 98,172 -derived hallucinogen 100 Ampicillin 61 Analysis, regression 129 Analytical methods 21,196 Anaphylactic reaction 186 Androsterone 16 Angina 278 Animal models for anti-inflamma tory drugs 168 Animal sources, drugs from 14 Antiarrhythmic agents 92, 278 Antibacterial antibiotics 40 cogeners of 66 novel 46 drug discoveries, projection of . . 68 approaches to 50, 63 microbial metabolite discoveries 38 Antibiotics 198,213 antibacterial 40 cogeners of antibacterial 66 inhibitory action of known . . . . 71 produced by fermentation . . . . 179 selective toxicity of 69 structural modification of 51,63

Antidepressants 94 Anti-infectives 198 Anti-inflammatory compounds . . . 169 animal models for 168 Antihistamines 86, 198 Antileukemic principle of Jatropha gossypiifolia

10

Antimalarial activity 135 Antimicrobial activity of actinomycetes 34-5 of bacteria 36-7 of fungi 34-5 of molds 34-5 drugs 83 Antitumor drugs 241 6-APA 58 Approaches to drug design, physicochemical 123 Aromatic functional groups, parameters for 108 Arthritis 17,168 Aspirin 169,197 Assay, biological 196 Asthma, Ε prostaglandins for . . . . 29 Β Bacteria, antimicrobial activity of . . 36-7 Behavioral pharmacology 167 Benefit-to-risk ratio 283 Benzylpenicillinase 60 Bergstrom, S 25 Bile acids 31 Biochemical pharmacology in drug discovery 93 Biochemical rationales, receptor mechanisms and 141 Biodetection 15 Biogenic amines 93 Biological assay 196 concept of selective toxicity . . . . 83 knowledge gap 166 Biologically active plant constituents 1 Biology molecular 170,171,190 quantum 132 Biomedical R & D 220,234 Biosynthesis of NE 90 of neurohormones 89 structural modification by 62 Bruice, T. C 125 Bureau of Drugs 248

289

Bloom and Ullyot; Drug Discovery Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

290

DRUG DISCOVERY


Business parameters Butenandt, A

212 16,24

C Cammarata, A 134 Carbenicillin 62 Cancer chemotherapy 241 drugs 182 of the nasopharynx 7, 9 Cardiac arrhythmias 182, 227 Catecholamine 145 Catron 95 Center for Population Research . . 244 Cephalosporins 185 semisynthetic 63 Chemical Abstracts Service 243 Chemical mediators 88 Chemical species, evolutionary variation in 30 Chemistry, quantum 132 Chemotherapy 196 cancer 241 Cholinergic systems 148 Chloramphenicol 52 Cholesterol 18,20,31 Cinchona 3 CNDO/2 treatment 104 CNS 98 Committee on Problems of Drug Safety 173 Communication between industry and the physician 271 Concentration of prostaglandins . . 25 Concentrations of steroid hormones, source 16 Congeners of antibacterial antibiotics 66 Congressional hearings 207 Contraceptives 244 Cook, J. W 18 Cortisone 17 Costs, promotional 262 and distribution 279 of research 276 Cotzias, M. C 170 Crum-Brown studies 124 Crystallography, x-ray 190 Current drugs 169 Cycloserine 48 D Decarboxylase, inhibitors of 6-Deoxytetracycline Depression, mental Derivatives of dopamine Development and discovery of steroid hormones of drugs Diabetes Diethylstilbestrol Digitalis

96 54, 56 167 91 17 269 123 18 185

Discoveries antibacterial microbial metabolite 38 and development of steroid hormones 17 drug 200,220 rate of 176,192 of morphine 2 Disease processes 160 Dithiothreitol 148 DNA 170 DOPA 88,92 L-Dopa 170, 222,253,255 Dopamine 92,170,222 derivatives of 91 DPA 149 Drug (see also Drugs) abuse 172 action 169 mechanism of 214 -biogenic amine interaction, neuronal pathways 97 -designed diuretic 100 design, physicochemical approaches to 102,123 development, government regulations and 247 discovery 220 approaches to antibacterial . . 63 future of 209 projection of antibacterial . . . . 63 process of 200 proposed approaches to antibacterial 50 rate of 176, 192 role of biochemical pharmacology in 93 synthetic 82 Efficacy Study 173 entities, available 19 evaluation 205 interactions 173 Law Amendments 181 lipophilicity 56 metabolism 170 approach 98 studies 170 receptor 106 interaction 83, 143 registration system 208 research 213 the future of the synthetic approach in 109 organization 179 planning 121 rational 117 Safety, Committee on Problems of 173 surveillance program 242 Drugs (see also Drug) /3-adrenergic blocking 92 the American system of 195 animal models for antiinflammatory 168


291


INDEX

Drugs (Continued) from animal sources 14 antimicrobial 83 antitumor 241 appearance of new 252 Bureau of 248 cancer 182 development of 269 efficacy of 171,191,217,249 future of 183 generic 202 immunologic effects of 172 incapacitating 186 insecticidal 83 and medical practice 267 from microbiological sources . . . 33 needs for new 112 neurotransmitters as source of new synthetic 87 new 224-5,273 and potential 1 from plants 1,119, 185 safety of 171,191,217,249 for tumors 242 use of 269

Ε Economic image of the pharma ceutical industry 257 Efficacy of drugs . . . . 171,191, 217,249 Ehrlich, Paul 82,197 Electron density 134 Enzymological mechanistic concepts 120 Ε prostaglandins, use in asthma . . 29 Equation, ρ-σ-ττ 128 Erythromycin 50 Estrone 15 Ethacrynic acid 100 Evaluation, drug 205 Evolutionary variation in chemical species 30 Evolution of medicines 196 Expenditures, R & D 212 Extended Huckel Theory 104 Extrathermodynamic approach . . 131, 142 F False transmitters 98 Fatty acid technology 24,28 FDA (see Food and Drug Admin istration ) Ferguson, J 124 Fermentation, antibiotics produced by 179 9-Fluoro analog of hydrocortisone 18 Food and Drugs Act 178,199, 247 Amendments to the 214 Food and Drug Administration (FDA) ....114,181,191,200,216, 243,247, 253, 261, 269,279, 282 history of the 247 Food, Drug, and Cosmetic Act . . . 205 amendments to the 247

Free energy 134 Free, S. M 125 Free-Wilson 127 Fried, J 18 Fuhner, H 124 Fungi, antimicrobial activity of . . . 34-5 classes of 51 Future of drug discovery 209 of drugs 183 role of microbial metabolites . . 72 G Generic drug names Genetic damage Gibbs free energy Goldblatt, M. W Gout Government regulation Government, role of Government support Growth-inhibitory activity

202, 273 171 128 25 98,169,182 204, 215, 247 223 228, 238 11

H Hammett equation 127, 128 Hansch, C 102,130 Hansch approach 102,106 Haptophoric moiety 83 Health research, role of NIH in . . 233 HEW economists 280 Histamine 84 History of the FDA 247 Homeopathy 198 Hormones, steroid 15 discovery and development . . . . 17 source concentrations of 16 Huckel molecular orbital method . . 135 Hydrocortisone, 9-fluoro analog of 18 Hypertension and mental disease, Rauwolfia alkaloids for 4 I Immunologic effects of drugs . . . . 172 Incapacitating drugs 186 Inhibitors of decarboxylase 96 Inhibitory action of known antibiotics 71 Insecticidal drugs 83 Instrumental and analytical techniques 21,114,135 Interactions, drug 173 International regulations 208 Intrinsic activity 82 Inventions, patentable 244 Isolation of new microbial metabolites 67 Isoniazid 221 J Jatropha gossypiifolia, antileukemic

principle of latrophone


10 6

292

DRUG DISCOVERY

Κ Kefauver -Harris Amendment hearings Ketamine Kier approach Kinetic approaches Kopecky, J Kurzrok, R

178 216 255 106 143 127 23


L /3-Lactam 49,182,186 Librium 187 Lieb, C. C 23 Linear free-energy related model.. 127 Lithium ion 98 LSD 127 M Malaria 3 Malathion 99 MAO 120,222 inhibitors . 98 Marijuana 172 Mathematical structure-activity model 127 McGowan, J. C 125 Mechanism of drug action 214 Mechanisms and biochemical rationales, receptor 141 Mediators of physiologic functions 88 Medical practice, drugs and 267 Medical Scientist Program 229 Medicines the American system of 195 evolution of 196 and politics 207 MEDLARS 244 Megalomycin A 50 Mental disease and hypertension, Rauwolfia alkaloids for 4 Merck Index 243 Metabolism, drug 170 of malathion 99 Metabolite discoveries, antibacterial microbial 38 microbial 70 Methamphetamine 95 Methodology 114 Methods analytical 196 instrumental 135 α-Methyl-N-aminodopa 96 α-Methylene lactone function . . . . 7 Meyer, Κ. H 124 Meyer-Overton theory 102 Microbial metabolites 70 discoveries, antibacterial 38 future role of 72 isolation of new 67 Microbiological 11-oxygenation . . 18 Microbiological sources, drugs from 33 :

Model, mathematical structureactivity 127 Models for anti-inflammatory drugs, animal 168 Molds, antimicrobial activity of . . 34-5 Molecular approaches 144 biology 170,171,190 modification 117,179,280 of prototypes 187 orbital method, Huckel 135 orbital parameters 188 theory 104,132 Molecular quasi-symmetry 158 Moore, W 124 Morphine, discovery of 2 Multiple regression technique . . . 104 Mycobacterium adjuvant arthritis test 168

Ν Narcotics 172 NAS-NRC (see National Academy of Sciences-National Research Council ) Nasopharynx, carcinoma of 7,9 National Academy of Sciences-Na tional Research Council . . .217, 250 National Cancer Institute 233 National Institutes of Health 184,187,229,233 National Library of Medicine 243 National Research Council, role of 251 Naturally occurring prostaglandins and their precursors 22-3 NDA (see New Drug Application) NE (see Norepinephrine Neurohormones, biosynthesis of . . 89 Neuroleptics 167 Neuronal pathways in drug-biogenic amine interaction 97 Neurotransmitters as a source of new synthetic drugs 87 New drugs 224-5,273 appearance of 252 needs for 112 organic synthesis as a source of 81 and potential drugs 1 New Drug Application ( NDA ) . . . . 178,183,192, 200, 252 New product introductions, rate of 178 New synthetic drugs, the neuro transmitters as source of . . . . 87 NIH (see National Institutes of Health) NMR 135 Norepinephrine (NE) 89,145,222 biosynthesis 90 Ο Occurrence of prostaglandins


25

293

INDEX

Organic compounds, synthesis of . . as a source of new drugs . . . . . . Organic mercurials Original discoveries Origin of pharmaceuticals Orthostatic hypotension Overton, Ε 11-Oxygenation, microbiological . .

68 81 100 284 197 98 124 18


Ρ

Pseudomonas

PAM 101 Parachors 125 Parameters for aromatic functional groups . . 108 business 212 electronic 132 molecular orbital 188 physicochemical 124 steric 133 transport 132 Parkinsons disease 98,170,222 Partition coefficient 104 Partitioning properties 124 Patents 202 for inventions 244 role of 261 Penicillins 180,186 acid-stable 60 semisynthetic 57 Periwinkle plant 5 Pharmaceutical industry 270 economic image of the 257 operation of 270 R & D in the 211 Pharmaceutical Manufacturers' Association 212 Pharmaceutical research 200, 258 Pharmaceuticals, origin of 197 Pharmacology, behavioral 167 Pharmacology-Toxicology Program 173,242 Phenacetin 197 PGEi 27 PGE 29 y

2

P. homomalla

Propranolol 183 Prostaglandins concentration of 25 discovery and development . . . . 26—7 naturally occurring precursors of 22-3 occurrence of 25 structure of 22-3 Prostanoic acid, synthesis of 29 Prototypes, molecular modification of 187

31

Physicochemical approaches to drug design 102,123 Physicochemical parameter 124 Plant constituents, biologically active 1 origin, tumor inhibitors of 6 sources, drugs from 185 drugs from 1, 119 Postgraduate education 272 Precursors of steroid hormones . . 20 Procaine 198,277 Processes, disease 169 Progesterone 16 Program, Pharmacology-Toxicology 173 Promotional costs 262 and distribution costs 279 Properties, partitioning 124

fluorenscens

48

Psychotherapeutic agents 166 Pure Food and Drug Act ( see Food and Drugs Act ) Q Quantum biology chemistry mechanical approaches Quinine

132 132 107 2,227

R Random screening 189 Rate of drug discovery 176,192 of new product introductions . . 178 Rational drug research 117 Rauwolfia

113

alkaloids for hypertension and mental disease 4 R&D 276 biomedical 235 budget 277 expenditures 212,259 investment 258 in the pharmaceutical industry . . 211 programs 254 Receptor 83 a152 β154 mechanisms and biochemical rationales 141 theory 82 Registration system, drug 208 Regression analysis 129 Regulations and drug development, government 247 government 204,215 international 208 Regulatory 114 Research adrenal steroid 17 biomedical 220 cost of 276 drug 213 organizations, drug 179 pharmaceutical 200, 258 rational drug 117 role of NIH in health 233 viral 190


294

DRUG DISCOVERY

Reserpine 4,185 Richet, M 125 Rifamide 66 Rifamycins, semisynthetic 65 Role of National Research Council 251 Role of patents 261


S

Safety of drugs 171,191,217,249 Schizophrenia 168 Screening, random 189 Selective toxicity 82 of antibiotics 69 biological concept of 83 Semisynthetic drugs 182 cephalosporins 63 penicillins 57 rifamycins 65 tetracyclines 53 Sequential control sites, theory of . . 156 Serotonin 98 Side chain theory 82 Sigma constants 125 Source concentrations of steroid hormones 16 Squalene 18 Standards, regulatory 114 Steric parameters 133 Steroid hormones 15 development 18 discovery and development . . . 17 precursors of 20 Steroid research adrenal 17 timetable 21 Streptomyces 43 Structural modification of antibiotics 51 by biosynthetic methods 62 Structure of acetylcholinesterase . . 150 Structure-activity model, mathematical 127 relationships 102 studies 124 Structures of prostaglandin family 22-3 Substrate-receptor interactions . . . 136 Sulfonamides 85 Support, government 238 Symmetry equations 126 molecular quasi158 topographical 158 Sympathomimetic amines 89 Synthesis of organic compounds 68 of prostanoic acid 29

Synthetic approach in drug research, future of the ' drug discovery

109 82

Τ Taft, R. W 128 Taft substituent constant 105 Testosterone 16 Tetracycline 182 semisynthetic 53 Tetrology studies 214 Thalidomide 214,248 Theory of sequential control sites 156 Thorazine 284 Timetable, steroid research 21 Topographical symmetry 158 Toxicology Bibliography 244 Program, Pharmacology242 Toxiphilic moiety 83 Tradenames 273 Tranquilizers 98, 167 Transport parameters 133 therapy 180 3,4,5-Trimethoxyamphetamine . . . 99 Tumors drugs for 242 inhibitors of plant origin 6 U Use of drugs U. S. Pharmacopoeia

269 243

V

Valium Vernolepin Vincaleukoblastine Vincristine Viral research Vitamin therapy VMA von Euler, U. S

187 6 4 5 190 198 98 24,25

W Warburg, 0 Wieland, Η Wilson, J. W Windaus, A World Health Organization (WHO)

124 20 125 20,25 173,208

X X-ray crystallography


190

Drug Discovery

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