Chapter 1

Introduction

1.1 Medicinal Chemistry Folklore . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.2 Discovery of New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.3 General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1.1 Medicinal Chemistry Folklore

Medicinal chemistry is the science that deals with the discovery and design of new therapeuticchemicals and their development into useful medicines. Medicines are substances used to treatdiseases. Drugs are molecules used as medicines or as components in medicines to diagnose,cure, mitigate, treat, or prevent disease.[1] Medicinal chemistry may involve isolation of com-pounds from Nature or the synthesis of new molecules, investigations of the relationshipsbetween the structure of natural and/or synthetic compounds and their biological activities,elucidations of their interactions with receptors of various kinds, including enzymes and DNA,the determination of their absorption, transport, and distribution properties, and studies of themetabolic transformations of these chemicals into other chemicals and their excretion. Morerecently, genomics, the investigations of an organism’s genome (all of the organism’s genes)to identify important target genes and gene products (that is, proteins expressed by the genes),and proteomics, the investigations of new proteins in the organism’s proteome (all of theproteins expressed by the genome)[2] to determine their structure and/or function often bycomparison with known proteins, have become increasingly important approaches to identifynew drug targets.

Medicinal chemistry, in its crudest sense, has been practiced for several thousand years.Man has searched for cures for illnesses by chewing herbs, berries, roots, and barks. Someof these early clinical trials were quite successful; however, not until the last 100–150 yearshas knowledge of the active constituents of these natural sources been known. The earliestwritten records of the Chinese, Indian, South American, and Mediterranean cultures describedthe therapeutic effects of various plant concoctions.[3–5] A Chinese health science anthologycalled Nei Ching is thought to have been written by the Yellow Emperor in the 13th century b.c.,although some believe that it was backdated by the 3rd-century compilers.[6] The Assyriansdescribed on 660 clay tablets 1000 medicinal plants used from 1900–400 b.c.

Two of the earliest medicines were described about 5100 years ago by the Chinese EmperorShen Nung in his book of herbs called Pen Ts’ao.[7] One of these is Ch’ang Shan, the root

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2 Chapter 1 Introduction

Dichroa febrifuga, which was prescribed for fevers. This plant contains alkaloids that areused even today in the treatment of malaria. Another plant called Ma Huang (now knownas Ephedra sinica) contains ephedrine, a drug that raises the blood pressure and relievesbronchial spasms; this herb was used as a heart stimulant, a diaphoretic agent (perspirationproducer), and for treatment of asthma, hay fever, and nasal and chest congestion. It also isused today (unadvisably) by some body builders and endurance athletes because it promotesthemogenesis (the burning of fat) by release of fatty acids from stored fat cells, leading toquicker conversion of the fat into energy. Ephedra also tends to increase the contractile strengthof muscle fibers, which allows body builders to work harder with heavier weights.

Theophrastus in the 3rd-century b.c. mentioned opium poppy juice as an analgesic agent,and in the 10th-century a.d. Rhazes (Persia) introduced opium pills for coughs, mental disor-ders, aches, and pains. The opium poppy, Papaver somniferum, contains morphine, a potentanalgesic agent and codeine, which is prescribed today as a cough suppressant. The EastAsians and the Greeks used henbane, which contains scopolamine (truth serum) as a sleepinducer. Inca mail runners and silver miners in the high Andean mountains chewed coca leaves(cocaine) as a stimulant and euphoric. The antihypertensive drug reserpine was extracted byancient Hindus from the snakelike root of the Rauwolfia serpentina plant and was used totreat hypertension, insomnia, and insanity. Alexander of Tralles in the 6th-century a.d. rec-ommended the autumn crocus (Colchicum autumnale) for relief of pain of the joints, and itwas used by Avrienna (11th-century Persia) and by Baron Anton von Storck (1763) for thetreatment of gout. Benjamin Franklin heard about this medicine and brought it to America.The active principle in this plant is the alkaloid colchicine, which is used today to treat gout.

In 1633 a monk named Calancha, who accompanied the Spanish Conquistadors to Centraland South America, introduced one of the greatest herbal medicines to Europe on his return.The South American Indians would extract the cinchona bark and use it for chills and fevers;the Europeans used it for the same and for malaria. In 1820 the active constituent was isolatedand later determined to be quinine, an antimalarial drug.

Modern therapeutics is considered to have begun with an extract of the foxglove plant,which was cited by Welsh physicians in 1250, named by Fuchsius in 1542, and introducedfor the treatment of dropsy (now called congestive heart failure) in 1785 by Withering.[3,8]

The active constituents are secondary glycosides from Digitalis purpurea (the foxglove plant)and Digitalis lanata, namely, digitoxin and digoxin, respectively, both important drugs forthe treatment of congestive heart failure. Today, digitalis, which refers to all of the cardiacglycosides, is still manufactured by extraction of foxglove and related plants.

1.2 Discovery of New Drugs

Nature is still an excellent source of new drugs or, more commonly, of precursors to drugs. Ofthe 20 leading drugs in 1999, 9 of them were derived from natural products.[9] Almost 40% ofthe 520 new drugs approved for the drug market between 1983 and 1994 were natural productsor derived from natural products. Greater than 60% of the anticancer and anti-infective agentsthat are on the market or in clinical trials are of natural product origin or derived from naturalproducts.[10] This may be a result of the inherent nature of these secondary metabolites toact in defense of their producing organisms; for instance, a fungal natural product might beproduced against bacteria or other fungi or against cell replication of foreign organisms.[11]

Typically, when a natural product is found to be active, it is chemically modified to improveits properties. As a result of advances made in synthesis and separation methods and in

Section 1.3 General References 3

Figure 1.1 � “That’s Dr Arnold Moore. He’s conducting an experiment to test the theory that most greatscientific discoveries were hit on by accident.”Drawing by Hoff; c© 1957The New Yorker Magazine, Inc.

biochemical techniques since the late 1940s, the early random approach to drug discovery(Figure 1.1) was supplanted by a more rational approach, namely, one that involves the elementof design. A discussion of how drugs are discovered and chemically modified to improve orchange their medicinal properties is presented in Chapter 2. As we will see, the randomapproach still is important!

1.3 General References

The following references are excellent sources of material for this entire book.

Journals

Annual Reports in Medicinal Chemistry;Academic Press, San DiegoAnnual Review of BiochemistryAnnual Review of Medicinal ChemistryBiochemical PharmacologyBioorganic and Medicinal ChemistryBioorganic and Medicinal Chemistry LettersChemistry & BiologyCurrent Drug MetabolismCurrent Drug TargetsCurrent GenomicsCurrent Medicinal ChemistryCurrent Opinion in Chemical BiologyCurrent Opinion in Drug Discovery andDevelopment

Current Opinion in Investigational DrugsCurrent Opinion in Therapeutic PatentsCurrent Pharmaceutical BiotechnologyCurrent Pharmaceutical DesignCurrent Protein & Peptide ScienceDrug Design and DiscoveryDrug Development ResearchDrug Discovery and DevelopmentDrug Discovery TodayDrug News and PerspectivesDrugsDrugs of the FutureDrugs of TodayDrugs Under Experimental and ClinicalResearch

4 Chapter 1 Introduction

Emerging DrugsEmerging Therapeutic TargetsEuropean Journal of Medicinal ChemistryExpert Opinion on Investigational DrugsExpert Opinion on PharmacotherapyExpert Opinion on Therapeutic PatentsExpert Opinion on Therapeutic TargetsJournal of Medicinal ChemistryMedicinal Research ReviewsMini Reviews in Medicinal Chemistry

Modern Drug DiscoveryModern Pharmaceutical DesignMolecular PharmacologyNature MedicinePerspectives in Drug Discovery and DesignProgress in Drug ResearchProgress in Medicinal ChemistryTrends in Biochemical SciencesTrends in Pharmacological Sciences

Books

Advances in Medicinal Chemistry; Elsevier, New York; (continuing series).Albert, A. Selective Toxicity, 7th ed., Chapman and Hall, London, 1985.Arins, E. J. (Ed.) Drug Design, Academic, New York, 1971–1980, Vols. 1–10.Borchardt, R. T.; Freidinger, R. M.; Sawyer, T. K. Integration of Pharmaceutical Discovery

and Development: Case Histories, Plenum Press, New York, 1998.Burger, A. A Guide to the Chemical Basis of Drug Design, Wiley, New York, 1983.Hansch, C.; Emmett, J. C.; Kennewell, P. D.; Ramsden, C. A.; Sammes, P. G.; Taylor, J. B.

(Eds.) Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, 1990, Vols. 1–6.Hardman, J. G.; Limbird, L. E.; Gilman, A. G. (Eds.) Goodman and Gilman’s The

Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001.Lednicer, D. Chronicles of Drug Discovery, ACS, Washington, DC, 1993.Lednicer, D. Strategy for Organic Drug Synthesis and Design, Wiley, New York, 1998.Lednicer, D. Mitscher, L. A. The Organic Chemistry of Drug Synthesis, Wiley, New York,

1996, five-volume set.Lunn, G.; Schmuff, N. HPLC Methods for Pharmaceutical Analysis, Wiley-VCH, New York,

1997.Methods and Principles in Medicinal Chemistry, VCH, Weinheim. (continuing series).O’Neil, M. J.; Smith, A. (Eds.) The Merck Index, 13th ed., Merck & Co., Rahway, NJ, 2001.Wolff, M. E. (Ed.) Burger’s Medicinal Chemistry and Drug Discovery, John Wiley & Sons,New York, 1995–1997, Vols. 1–6.

1.4 References

1. Webster’s Ninth New Collegiate Dictionary, Merriam-Webster, Springfield, MA, 1987.

2. Wilkins, M. R.; Williams, K. L.; Appel, R. D.; Hochstrasser, D. F. (Eds.) ProteomeResearch: New Frontiers in Functional Genomics, Springer-Verlag, Berlin, 1997.

3. Bauer, W. W. Potions, Remedies and Old Wives’ Tales, Doubleday, New York, 1969.

4. Withering, W. An Account of the Foxglove and Some of Its Medicinal Uses: With Practi-cal Remarks on Dropsy and Other Diseases, Robinson, C. G. J., London, 1785; reprintedin Med. Class. 1937, 2, 305.

5. Sneader, W. Drug Discovery: The Evolution of Modern Medicines, Wiley, Chichester,1985.

Section 1.4 References 5

6. Nakanishi, K. In Comprehensive Natural Products Chemistry, Barton, D.; Nakanishi,K. (Eds.), Elsevier, Amsterdam and New York, 1999, Vol. 1, pp. xxiii–xl.

7. Chen, K. K. J. Am. Pharm. Assoc. 1925, 14, 189.

8. Burger, A. In Burger’s Medicinal Chemistry, 4th ed., Wolff, M. E. (Ed.), Wiley, NewYork, 1980, Part I, Chap. 1.

9. Harvey, A. Drug Discovery Today 2000, 5, 294.

10. Cragg, G. M.; Newman, D. J.; Snader, K. M. J. Nat. Prod. 1997, 60, 52.

11. Hung, D. T.; Jamison, T. F.; Schrieber, S. L. Chem. Biol. 1996, 3, 623.