1. The Organic Chemistry of Drug Design and Drug Action
Chapter 1
Introduction

2. Drug Discovery One way to “discover” drugs
Figure 1.1

3. Medicinal Chemistry
The science that deals with the discovery or design of new therapeutic agents and their development into useful medicines.
It involves:
Synthesis
Structure-Activity Relationships (SAR)
Receptor interactions
Absorption, distribution, metabolism, and excretion (ADME) and toxicology

4. Medicinal Chemistry Folklore
Earliest medicines ~ 5100 years ago
Chinese emperor Shen Nung - book of herbs, Pen Ts’ao
Modern therapeutics:
Extract of foxglove plant, cited by Welsh physicians in Used to treat dropsy (congestive heart failure) in 1785 Contains digitoxin and digoxin; today called digitalis
Ma Huang
Used as a heart stimulant and for nasal and chest congestion.
Contains ephedrine

5. Drugs from traditional sources

6. Quinine came from South America

7. Digitalis came from foxglove in Britain

8. Discovery of New Drugs
Nature is still an excellent source of new drugs (or precursors of new drugs).
Almost 40% of new drugs approved in the last 20 years are natural products or derived from natural products.
60% of antitumor and anti-infective drugs are natural products or derived from natural products.

9. Drug Discovery Without a Lead
Penicillins
Fleming
Bacteria lysed by green mold; could not reproduce effect - serendipity.
mold spore contaminates culture dish
left dish on bench top while on vacation
weather was unseasonably cold
particular strain of mold was a good penicillin producer
Could not get penicillin in a useful clinical form
Florey (Oxford)
Succeeded in producing penicillin in a useful clinical form.
Discovery was not published until late 1940’s after World War II so Germans would not benefit from it.

10. Structure of penicillin elucidated in 1944 - X-ray crystal structure by Dorothy Hodgkin (Oxford)

11. Sulfa antibiotics were discovered in 1935

12. Serendipitous Discovery of Librium without a Lead
In 1955 Roche set out to prepare a series of
benzheptoxdiazines (1.14) as potential new tranquilizer drugs, but the actual structure was found to be that of a
quinazoline 3-oxide (1.15).
No active compounds were found, so the project was abandoned

13. 1.16 was sent for testing, and it was highly active.
In 1957, during a lab cleanup, a vial containing what was thought to be
1.16 was sent for testing, and it was highly active.
Further analysis showed that the actual structure of the compound was
the benzodiazepine 4-oxide, 1.13, presumably produced in an
unexpected reaction of the corresponding chloromethyl quinazoline
3-oxide (1.16) with methylamine.
Scheme 1.1
Librium

14. Valium is a more active analogue of Librium

15. Drugs from Drug Metabolism Studies
The nonsedating antihistamine terfenadine
(Seldane) caused abnormal heart arrhythmias
in some patients (binds to hERG*), so it was
withdrawn from medical use.
*human Ether-a-go-go Related Gene
Fexofenadine (Allegra), a metabolite of
terfenadine, also is a nonsedating
antihistamine that does not cause heart
arrhythmias, so it replaced terfenadine

16. Sulindac is metabolized to the active compound (prodrug)

17. Drug Discovery from Clinical Observations
Viagra (sildenafil citrate) tested as antihypertensive/ antianginal drug.
Phase II trials not great, so went back to Phase I (healthy volunteers) at a higher dose.
Very happy volunteers .
Reported prolongation of penile erections

18. Mechanism of Action of Viagra
PDE 5
Phosphodiesterase
isozyme in corpus cavernosum (in penis)

19. Mechanism of Action of Viagra
PDE 5
Phosphodiesterase
isozyme in corpus cavernosum (in penis)

20. Dramamine and Zyban also were found from side effects in clinical trials

21. Rational Drug Discovery
Drugs generally are not discovered directly; first a lead compound is identified.
Lead compound
Prototype having desired activity but also other undesirable characteristics, e.g., toxicity, other activities, insolubility, metabolism problems, oral bioavailability
Lead modified by synthesis
to amplify desired activity
to minimize or eliminate undesirable properties
Produces a drug candidate (compound worthy of extensive biological, pharmacological, and animal testing)

22. Drug Discovery Average time to bring a drug to market is 12-15 years.
For every 20,000 compounds evaluated in animals, 10 make it to human clinical trials, of which 1 goes to market.

23. Lead Discovery First a bioassay (or screen) is needed
Means to determine in vitro or in vivo, relative to a control, whether the compound has the desired activity* and relative potency**.
* particular pharmacological effect (e.g., antibacterial effect)
** strength of the effect

24. Lead Discovery Approaches
1. Random screening - only approach before 1935; screen every compound you have; still a useful approach; streptomycin and tetracyclines identified in this way
2. Nonrandom (or Targeted or Focused) screening - only screen compounds related to active compounds
3. Drug metabolism studies - metabolites produced are screened for the same or other activities
4. Clinical observations - new activities found in clinical trials; Dramamine tested as antihistamine (allergy) - found to relieve motion sickness; Viagra tested as antihypertensive - found to treat erectile dysfunction

25. Lead Discovery Approaches (cont’d)
5. Rational approaches - identify causes for disease states:
imbalance of chemicals in the body
invasion of foreign organisms
aberrant cell growth
Identify biological systems involved in disease states; use natural receptor ligand or enzyme substrate as the lead; a known drug also can be used as a lead

26. Rational Drug Design Identify Target
Chemical imbalances - antagonism or agonism of a receptor; enzyme inhibition
Foreign organism and aberrant cell growth - enzyme inhibition; DNA interaction

27. Protein drug targets

28. Examples of drug target-dopamine D3 receptor
Figure 1.4 Small molecule drug (quinpirol) bound to its protein target (dopamine D3 receptor). The cartoon on the right shows how a protein, such as the D3 receptor, spans the membrane of a cell. The D3 receptor in red depicts its conformation when the drug is bound. The D3 receptor in yellow depicts its conformation when no drug is bound. “TM” designates a transmembrane domain of the protein. Note the significant differences between the red and yellow regions on the intracellular side of the membrane, prompted by the binding of quinpirol from the extracellular side (Ligia Westrich, et al. Biochem. Pharmacol. 2010, 79, 897–907.) On the right is a molecular representation of the fluid mosaic model of a biomembrane structure. From Singer, S. J.; Nicolson, G L. Science. 1972, 175, 720. Reprinted with permission from AAAS.

29. Example of drug target-DNA
Figure 1.5 Small molecule drug (daunomycin) bound to its nucleic acid target (DNA). The different colors represent C (yellow), G (green), A (red), and T (blue). Mukherjee, A.; Lavery, R.; Bagchi, B.; Hynes, J. T. On the molecular mechanism of drug intercalation into DNA: A computer simulation study of the intercalation pathway, free energy, and DNA structural changes. J. Am. Chem Soc. 2008, 130, Reprinted with permission from Dr. Biman Bagchi, Indian Institute of Science, Bangalore, India. Journal of the American Chemical Society by American Chemical Society. Reproduced with permission of American Chemical Society in the format republish in a book via Copyright Clearance Center.

30. Example of drug target-enzyme
Figure 1.6 Interaction of the drug zanamivir with its enzyme target neuraminidase. (a) Model derived from an X-ray crystal structure; zanamivir is depicted as a space-filling model at center: carbon (white), oxygen (red), nitrogen (blue), and hydrogen (not shown). Only the regions of the enzyme that are close to the inhibitor are shown: small ball and stick models show key enzyme side chains (b) Schematic two-dimensional representation showing noncovalent interactions (dotted-lines) between zanamivir and the enzyme.

31. The biosynthesis of cholesterol is a target for statin drugs

32. Acetylcholinesterase is a target for Alzheimer’s drugs

33. Problems with Targeted Approaches
Cannot predict toxicity/side effects.
Cannot predict transport/distribution.
Cannot predict metabolic fate.
Target in vivo may not be the desired one.

34. Drugs with unexpected targets
Ezetimibe--designed to inhibit cholesterol esterase, but inhibits cholesterol transport
Pregabalin—designed to activate Glu decarboxylase, but blocks Ca2+ channels

35. Alternatives to targets for lead discovery
Natural substrate or ligand—modify the structure to obtain desired property.
Natural product—can be adapted to bind to enzyme or receptor
Screening—screen large number of compounds to find those that have the desired property

36. Drug based on a natural ligand

37. Drug based on natural products

38. High-throughput Screens (HTS)
Very rapid, sensitive in vitro screens
Carried out robotically in or 3456-well titer plates on sub-microgram amounts of compound
Can assay 100,000 compounds a day
~ 200,000 compounds screened per year
~ 5-6  106 compounds screened per year
> 50  106 compounds screened per year
in a large pharmaceutical company
Increase in number of hits (compounds that elicit a predetermined level of activity)
So far, no increase in rate of the number of drugs coming on the market.

39. Other Screening Approaches
Possible to screen compounds for inhibition of an entire metabolic pathway:
Combine all enzymes in the pathway (e.g., bacterial cell wall biosynthesis), add compound, look for accumulation of an intermediate in the pathway (inhibition of the enzyme that acted on the intermediate).
Screening also done by electrospray ionization mass spectrometry.
Can add large number of compounds (as long as they have different molecular masses) and look for formation of noncovalent drug-receptor complexes in the mass spectrum. The affinity of the ligand (a small molecule that binds to a receptor) is measured by increasing the collision energy of the spectrometer.

40. Lead Modification
Pharmacodynamics Potency of drug binding to the target.
Pharmacokinetics ADME - Absorption, Distribution, Metabolism, Excretion; depends on water solubility and lipid solubility
Toxicity Often due to binding of the drug to unwanted off-targets—e.g., other enzymes or receptors.

41. Toxicity from off-target effects

42. Clinical Trials
Phase I (3-18 months) - evaluates safety, tolerability, pharmacokinetics, and pharmacological effects in healthy volunteers
Phase II (1-3 years) - assesses effectiveness, determines side effects and other safety aspects, clarifies dosing in a few hundred patients
Phase III (2-6 years) - establishes efficacy and adverse effects from long-term use with several thousand patients
New Drug Application (NDA) submitted to FDA (4-36 months)
Phase IV - results after drug is on market

43. Epilogue
For every 20,000 compounds tested in animals, 10 go to clinical trials, and 1 goes to market
12-15 years of research (constant since 1980)
Cost to get to market
$4 million
$350 million
$600-$800 million
$ billion
Only ~6000 known drugs of the estimated 1060 possible compounds

44. Epilogue (cont’d)
Only ~ different human targets known (< 1% of human proteome) - may be 5,000-10,000 potential drug targets
Genomics (identification of new gene targets) and proteomics (identification of proteins expressed) are new directions for drug discovery
In 2002, for the first time in U.S., generic drug sales were greater than nongeneric drug sales
In 2002, only 16 new drugs entered the market (usually 20s or 30s)
In 2013, 27 new drugs were approved

45. Number of New Drugs Declines as R&D Spending Increases
Year ‘04
New Drugs 36
‘05 20
‘06 22
‘07 17
‘08 24
‘09 25
‘10 21
‘11 35
‘12 39
‘13 27
‘14 41