0
Drug Discovery and
Development

How are drugs discovered and
developed?
• Choose a disease
• Choose a drug target
• Identify a “bioassay”
bioassay = A test used to determine biological
activity.
• Find a “lead compound”
“lead compound” = structure that has some
activity against the chosen target, but not yet
good en...
•
•
•
•

Synthesize analogs of the lead
Identify Structure-Activity-Relationships (SAR’s)
Synthesize analogs of the lead
I...
• Identify the “pharmacophore”
pharmacophore = the structural features directly
responsible for activity
• Optimize struct...
• Determine toxicity and efficacy in
animal models.
• Determine pharmacodynamics and
pharmacokinetics of the drug.
• Pharmacodynamics explores what a drug
does to the body, w...
• Patent the drug
• Continue to study drug metabolism
• Continue to test for toxicity
• Design a manufacturing process
• Carry out clinical trials
• Market the drug
Choosing a
Disease

• Pharmaceutical companies are
commercial enterprises
• Pharmaceutical companies will,
therefore, tend...
Choosing a
Disease
• Pharmaceutical companies
will also avoid products that
would be consumed by
individuals of lower econ...
Choosing a Disease (cont.)
• Most research is
carried out on diseases
which afflict “first world”
countries: (e.g. cancer,...
The Orphan Drug Act

• The Orphan Drug Act of 1983 was passed
to encourage pharmaceutical companies to
develop drugs to tr...
• Under this law, companies who develop
such a drug are entitled to market it without
competition for seven years.
• This ...
Identifying a Drug Target

• Drug Target = specific macromolecule,
or biological system, which the drug will
interact with...
Identifying a Drug Target (cont.)
•Example: In addition to their being able to inhibit the uptake
of noradrenaline, the ol...
The mapping of the human
genome should help!
• In the past, many medicines (and lead
compounds) were isolated from plant s...
• Having the genetic code for the production of an
enzyme or a receptor may enable us to overexpress that protein and dete...
Simultaneously, Chemistry is Improving!
• This is necessary, since,
ultimately, plants and natural
sources are not likely ...
Selectivity is Important!

• e.g. targeting a bacterial enzyme, which
is not present in mammals, or which
has significant ...
The Standards are Being Raised

• More is known about the biological
chemistry of living systems
• For example: Targeting ...
Problems can
arise

• Example: The chosen target, may over time,
lose its sensitivity to the drug
• Example: The penicilli...
Choosing the Bioassay
• Definitions:
– In vitro: In an artificial environment, as in a test
tube or culture media
– In viv...
Choosing the Bioassay (cont.)

In vitro testing
• Has advantages in terms of speed and requires
relatively small amounts o...
Choosing the Bioassay (cont.)

In vivo tests
• More expensive
• May cause suffering to animals
• Results may be clouded by...
Finding the Lead

Screening Natural Products
• Plants, microbes, the marine world, and
animals, all provide a rich source ...
• It is necessary to have a quick assay for
the desired biological activity and to be
able to separate the bioactive
compo...
Finding the Lead (cont.)

Screening synthetic banks
• Pharmaceutical companies have
prepared thousands of compounds
• Thes...
Finding the Lead (cont.)

Using Someone Else’s Lead
• Design structure which is similar to existing lead, but
different en...
Finding the Lead (cont.)
Enhance a side effect
O
H2N

S

NH2

O

sulphanilamide
(an antibacterial with the side effect of
...
Use structural similarity to a natural ligand

NH2

N(CH3)2
H
N

HO
H3C

S
O

N
H
5-Hydroxytryptamine (5-HT)
Serotonin (a ...
Computer-Assisted Drug Design
• If one knows the precise molecular structure of the
target (enzyme or receptor), then one ...
Serendipity: a chance occurrence
• Must be accompanied by an experimentalist who
understands the “big picture” (and is not...
Finding a Lead (cont.)
Sildenafil (compound UK-92,480) was synthesized by a
group of pharmaceutical chemists working at Pf...
Pfizer therefore decided to market it for erectile dysfunction, rather
than for angina.
The drug was patented in 1996, app...
Finding a Lead (cont.)

O
N
N
N
NH
O
O

S
O
N

N

viagra
(Sildenafil)
Structure-Activity-Relationships (SAR’s)

• Once a lead has been discovered, it is important to
understand precisely which...
The pharmacophore is the precise section of the
molecule that is responsible for biological activity
•
•
•
•
•

This may enable one to prepare a more active molecule
This may allow the elimination of “excessive” functionali...
Link
Next step: Improve
Pharmacokinetic Properties
• Improve pharmacokinetic properties.
pharmacokinetic = The study of absorpt...
Metabolism of Drugs
• The body regards drugs
as foreign substances,
not produced naturally.
• Sometimes such
substances ar...
Metabolism of Drugs (cont.)
• Phase 1 Metabolism involves the
conversion of nonpolar bonds (eg C-H
bonds) to more polar bo...
Mechanism of Cytochrome
P450
Phase I metabolism may
either detoxify or toxify.
• Phase I reactions produce a more polar
molecule that is easier to elim...
The Liver
• Oral administration frequently brings the
drugs (via the portal system) to the liver
Metabolism of Drugs (cont.)
• Phase II metabolism links the drug to still
more polar molecules to render them even
more ea...
Metabolism of Drugs (cont.)
• Another Phase II reaction is sulfation
(shown below)

NH2
N
O
O
R

OH

S
O-

N

O
O

P

O

N...
Phase II Metabolism
• Phase II reactions most commonly
detoxify
• Phase II reactions usually occur at polar
sites, like CO...
Manufacture of Drugs

•
•
•
•

Pharmaceutical companies must make a profit to continue to exist
Therefore, drugs must be s...
•

•
•

The route must be suitable to the
“scale up” needed for the production of
at least tens of kilograms of final
prod...
Toxicity
• Toxicity standards are continually becoming
tougher
• Must use in vivo (i.e. animal) testing to screen for
toxi...
Example: Thalidomide
Thalidomide was developed by German pharmaceutical
company Grünenthal. It was sold from 1957 to 1961 ...
Birth defects
caused by use of thalidomide
Example: Thalidomide
From 1956 to 1962, approximately 10,000 children were born with
severe malformities, including phocom...
Example: Thalidomide
•Researchers, however, continued to work with the drug. Soon
after its banishment, an Israeli doctor ...
Thalidomide
Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller
University in New York City showed that thal...
Clinical Trials
• Phase I: Drug is tested on healthy volunteers
to determine toxicity relative to dose and to
screen for u...
Clinical Trials
• Phase II: Drug is tested on small group of patients
to see if drug has any beneficial effect and to
dete...
Clinical Trials
• Phase III: Drug is tested on much larger
group of patients and compared with existing
treatments and wit...
Clinical Trials
• Phase IV: Drug is placed on the market and patients
are monitored for side effects
Assigned Reading
• Haffner Marlene E; Whitley Janet; Moses Marie Two decades
of orphan product development. Nature reviews...
Optional Additional Reading
• Bartlett J Blake; Dredge Keith; Dalgleish Angus G The
evolution of thalidomide and its IMiD ...
Homework Questions
• What is an ‘orphan drug’. Why has the Orphan Drug Act been
successful?
• Thalidomide is actually a mi...
Drug discoverydevelopment2011
Drug discoverydevelopment2011
Drug discoverydevelopment2011
Drug discoverydevelopment2011
Drug discoverydevelopment2011
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Transcript of "Drug discoverydevelopment2011"

  1. 1. Drug Discovery and Development How are drugs discovered and developed?
  2. 2. • Choose a disease • Choose a drug target • Identify a “bioassay” bioassay = A test used to determine biological activity.
  3. 3. • Find a “lead compound” “lead compound” = structure that has some activity against the chosen target, but not yet good enough to be the drug itself. • If not known, determine the structure of the “lead compound”
  4. 4. • • • • Synthesize analogs of the lead Identify Structure-Activity-Relationships (SAR’s) Synthesize analogs of the lead Identify Structure-Activity-Relationships (SAR’s)
  5. 5. • Identify the “pharmacophore” pharmacophore = the structural features directly responsible for activity • Optimize structure to improve interactions with target
  6. 6. • Determine toxicity and efficacy in animal models.
  7. 7. • Determine pharmacodynamics and pharmacokinetics of the drug. • Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug.
  8. 8. • Patent the drug • Continue to study drug metabolism • Continue to test for toxicity
  9. 9. • Design a manufacturing process • Carry out clinical trials • Market the drug
  10. 10. Choosing a Disease • Pharmaceutical companies are commercial enterprises • Pharmaceutical companies will, therefore, tend to avoid products with a small market (i.e. a disease which only affects a small subset of the population)
  11. 11. Choosing a Disease • Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries)
  12. 12. Choosing a Disease (cont.) • Most research is carried out on diseases which afflict “first world” countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine, obesity).
  13. 13. The Orphan Drug Act • The Orphan Drug Act of 1983 was passed to encourage pharmaceutical companies to develop drugs to treat diseases which affect fewer than 200,000 people in the US
  14. 14. • Under this law, companies who develop such a drug are entitled to market it without competition for seven years. • This is considered a significant benefit, since the standards for patent protection are much more stringent.
  15. 15. Identifying a Drug Target • Drug Target = specific macromolecule, or biological system, which the drug will interact with • Sometimes this can happen through incidental observation…
  16. 16. Identifying a Drug Target (cont.) •Example: In addition to their being able to inhibit the uptake of noradrenaline, the older tricyclic antidepressants were observed to “incidentally” inhibit serotonin uptake. Thus, it was decided to prepare molecules which could specifically inhibit serotonin uptake. It wasn’t clear that this would work, but it eventually resulted in the production of fluoxetine (Prozac). HO NH2 N N CH3 H3C Imipramine (a classical tricyclic antidepressant) N H serotonin F3C HN O prozac
  17. 17. The mapping of the human genome should help! • In the past, many medicines (and lead compounds) were isolated from plant sources. • Since plants did not evolve with human beings in mind, the fact that they posses chemicals which results in effects on humans is incidental.
  18. 18. • Having the genetic code for the production of an enzyme or a receptor may enable us to overexpress that protein and determine its structure and biological function. If it is deemed important to the disease process, inhibitors (of enzymes), or antagonists or agonists of the receptors can be prepared through a process called rational drug design.
  19. 19. Simultaneously, Chemistry is Improving! • This is necessary, since, ultimately, plants and natural sources are not likely to provide the cures to all diseases. • In a process called “combinatorial chemistry” large numbers of compounds can be prepared at one time. • The efficiency of synthetic chemical transformations is improving.
  20. 20. Selectivity is Important! • e.g. targeting a bacterial enzyme, which is not present in mammals, or which has significant structural differences from the corresponding enzyme in mammals
  21. 21. The Standards are Being Raised • More is known about the biological chemistry of living systems • For example: Targeting one subtype of receptor may enable the pharmaceutical chemist to avoid potentially troublesome side effects.
  22. 22. Problems can arise • Example: The chosen target, may over time, lose its sensitivity to the drug • Example: The penicillin-binding-protein (PBP) known to the the primary target of penicillin in the bacterial species Staphylococcus aureus has evolved a mutant form that no longer recognizes penicillin.
  23. 23. Choosing the Bioassay • Definitions: – In vitro: In an artificial environment, as in a test tube or culture media – In vivo: In the living body, referring to tests conductedin living animals – Ex vivo: Usually refers to doing the test on a tissue taken from a living organism.
  24. 24. Choosing the Bioassay (cont.) In vitro testing • Has advantages in terms of speed and requires relatively small amounts of compound • Speed may be increased to the point where it is possible to analyze several hundred compounds in a single day (high throughput screening) • Results may not translate to living animals
  25. 25. Choosing the Bioassay (cont.) In vivo tests • More expensive • May cause suffering to animals • Results may be clouded by interference with other biological systems
  26. 26. Finding the Lead Screening Natural Products • Plants, microbes, the marine world, and animals, all provide a rich source of structurally complex natural products.
  27. 27. • It is necessary to have a quick assay for the desired biological activity and to be able to separate the bioactive compound from the other inactive substances • Lastly, a structural determination will need to be made
  28. 28. Finding the Lead (cont.) Screening synthetic banks • Pharmaceutical companies have prepared thousands of compounds • These are stored (in the freezer!), cataloged and screened on new targets as these new targets are identified
  29. 29. Finding the Lead (cont.) Using Someone Else’s Lead • Design structure which is similar to existing lead, but different enough to avoid patent restrictions. • Sometimes this can lead to dramatic improvements in biological activity and pharmacokinetic profile. (e.g. modern penicillins are much better drugs than original discovery).
  30. 30. Finding the Lead (cont.) Enhance a side effect O H2N S NH2 O sulphanilamide (an antibacterial with the side effect of lowering glucose levels in the blood and also diuretic activity) N Cl O O S NH O NH tolbutamide (a compound which has been optimized to only lower blood glucose levels. Useful in the treatment of Type II diabetes.) O H2N NH S S O O O Chlorothiazide (a compound which has been optimized to only display diuretic activity.)
  31. 31. Use structural similarity to a natural ligand NH2 N(CH3)2 H N HO H3C S O N H 5-Hydroxytryptamine (5-HT) Serotonin (a natural neurotransmitter synthesized in certain neurons in the CNS) O N H Sumatriptan (Imitrex) Used to treat migrain headaches known to be a 5-HT1 agonist
  32. 32. Computer-Assisted Drug Design • If one knows the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly-fitting ligand. • Drawbacks: Most commercially available programs do not allow conformational movement in the target (as the ligand is being designed and/or docked into the active site). Thus, most programs are somewhat inaccurate representations of reality.
  33. 33. Serendipity: a chance occurrence • Must be accompanied by an experimentalist who understands the “big picture” (and is not solely focused on his/her immediate research goal), who has an open mind toward unexpected results, and who has the ability to use deductive logic in the explanation of such results. • Example: Penicillin discovery • Example: development of Viagra to treat erectile dysfunction
  34. 34. Finding a Lead (cont.) Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a form of ischaemic cardiovascular disease). Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.
  35. 35. Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.
  36. 36. Finding a Lead (cont.) O N N N NH O O S O N N viagra (Sildenafil)
  37. 37. Structure-Activity-Relationships (SAR’s) • Once a lead has been discovered, it is important to understand precisely which structural features are responsible for its biological activity (i.e. to identify the “pharmacophore”)
  38. 38. The pharmacophore is the precise section of the molecule that is responsible for biological activity
  39. 39. • • • • • This may enable one to prepare a more active molecule This may allow the elimination of “excessive” functionality, thus reducing the toxicity and cost of production of the active material This can be done through synthetic modifications Example: R-OH can be converted to R-OCH3 to see if O-H is involved in an important interaction Example: R-NH2 can be converted to R-NH-COR’ to see if interaction with positive charge on protonated amine is an important interaction
  40. 40. Link
  41. 41. Next step: Improve Pharmacokinetic Properties • Improve pharmacokinetic properties. pharmacokinetic = The study of absorption, distribution, metabolism and excretion of a drug (ADME). • Video • exercise=MedicationDistribution&title=Medica tion%20Absorption,%20Distribution, %20Metabolism%20and%20Excretion %20Animation&publication_ID=2450
  42. 42. Metabolism of Drugs • The body regards drugs as foreign substances, not produced naturally. • Sometimes such substances are referred to as “xenobiotics” •Body has “goal” of removing such xenobiotics from system by excretion in the urine •The kidney is set up to allow polar substances to escape in the urine, so the body tries to chemically transform the drugs into more polar structures.
  43. 43. Metabolism of Drugs (cont.) • Phase 1 Metabolism involves the conversion of nonpolar bonds (eg C-H bonds) to more polar bonds (eg C-OH bonds). • A key enzyme is the cytochrome P450 system, which catalyzes this reaction: RH + O2 + 2H+ + 2e– → ROH + H2O
  44. 44. Mechanism of Cytochrome P450
  45. 45. Phase I metabolism may either detoxify or toxify. • Phase I reactions produce a more polar molecule that is easier to eliminate. • Phase I reactions can sometimes result in a substance more toxic than the originally ingested substance. • An example is the Phase I metabolism of acetonitrile
  46. 46. The Liver • Oral administration frequently brings the drugs (via the portal system) to the liver
  47. 47. Metabolism of Drugs (cont.) • Phase II metabolism links the drug to still more polar molecules to render them even more easy to excrete UDP Glucuronic Acid Glucuronic Acid HO O HO O O P O P O O O NH O glucuronosyltransferase enzyme N HO OH OH O Drug O HO R O HO HO O O HO OH OH OH More easily excreted than ROH itself R OH Drug
  48. 48. Metabolism of Drugs (cont.) • Another Phase II reaction is sulfation (shown below) NH2 N O O R OH S O- N O O P O N O O- N SO3R Drug O O P OH O- O- 3'-Phosphoadenosine-5'-phosphosulfate O Sulfated Drug (more easily excreted)
  49. 49. Phase II Metabolism • Phase II reactions most commonly detoxify • Phase II reactions usually occur at polar sites, like COOH, OH, etc.
  50. 50. Manufacture of Drugs • • • • Pharmaceutical companies must make a profit to continue to exist Therefore, drugs must be sold at a profit One must have readily available, inexpensive starting materials One must have an efficient synthetic route to the compound – As few steps as possible – Inexpensive reagents
  51. 51. • • • The route must be suitable to the “scale up” needed for the production of at least tens of kilograms of final product This may limit the structural complexity and/or ultimate size (i.e. mw) of the final product In some cases, it may be useful to design microbial processes which produce highly functional, advanced intermediates. This type of process usually is more efficient than trying to prepare the same intermediate using synthetic methodology.
  52. 52. Toxicity • Toxicity standards are continually becoming tougher • Must use in vivo (i.e. animal) testing to screen for toxicity – Each animal is slightly different, with different metabolic systems, etc. – Thus a drug may be toxic to one species and not to another
  53. 53. Example: Thalidomide Thalidomide was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies. Antiemetic = a medication that helps prevent and control nausea and vomiting
  54. 54. Birth defects caused by use of thalidomide
  55. 55. Example: Thalidomide From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy. In 1962, in reaction to the tragedy, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S. O N O NH O O Thalidomide presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet. Phocomelia
  56. 56. Example: Thalidomide •Researchers, however, continued to work with the drug. Soon after its banishment, an Israeli doctor discovered antiinflammatory effects of thalidomide and began to look for uses of the medication despite its teratogenic effects. •He found that patients with erythema nodosum leprosum, a painful skin condition associated with leprosy, experienced relief of their pain by taking thalidomide. Teratogenic = Causing malformations in a fetus
  57. 57. Thalidomide Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller University in New York City showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha. Kaplan partnered with Celgene Corporation to further develop the potential for thalidomide. Subsequent research has shown that it is effective in multiple myeloma, and it is now approved by the FDA for use in this malignancy. There are studies underway to determine the drug's effects on arachnoiditis, Crohn's disease, and several types of cancers.
  58. 58. Clinical Trials • Phase I: Drug is tested on healthy volunteers to determine toxicity relative to dose and to screen for unexpected side effects
  59. 59. Clinical Trials • Phase II: Drug is tested on small group of patients to see if drug has any beneficial effect and to determine the dose level needed for this effect.
  60. 60. Clinical Trials • Phase III: Drug is tested on much larger group of patients and compared with existing treatments and with a placebo
  61. 61. Clinical Trials • Phase IV: Drug is placed on the market and patients are monitored for side effects
  62. 62. Assigned Reading • Haffner Marlene E; Whitley Janet; Moses Marie Two decades of orphan product development. Nature reviews. Drug discovery (2002), 1(10), 821-5. Link • Franks Michael E; Macpherson Gordon R; Figg William D Thalidomide. Lancet (2004), 363(9423), 1802-11. Link • Abou-Gharbia, Magid. Discovery of innovative small molecule therapeutics. Journal of Medicinal Chemistry (2009), 52(1), 2-9. Link • Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nature Reviews Drug Discovery (2010), 9: 203-214. • Jorgensen, W. L. The many roles of computation in drug discovery. Science (2004) 303: 1813-1818. • Butcher, E. C. et al. Systems biology in drug discovery. Nature biotechnology (2004) 22(10): 1253-1259.
  63. 63. Optional Additional Reading • Bartlett J Blake; Dredge Keith; Dalgleish Angus G The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nature reviews. Cancer (2004), 4(4), 314-22. Link • Cragg, G. M.; Newman, D. J. Nature: a vital source of leads for anticancer drug development. Phytochemistry Reviews (2009), 8(2), 313-331. Link • Betz, U. A. K. et al. Genomics: success or failure to deliver drug targets? Current Opinion in Chemical Biology (2005), 9: 387-391 • Sams-Dodd, F. Target-based drug discovery: is something wrong? Drug Discovery Today (2005) 10: 139-147.
  64. 64. Homework Questions • What is an ‘orphan drug’. Why has the Orphan Drug Act been successful? • Thalidomide is actually a mixture of two compounds. Draw their structures and list the physiological effects of each. • What does ADMET stand for? • List several possible reasons for poor efficacy of drug candidates in in vivo models. • Explain how structure-based design was used to develop an inhibitor with improved selectivity for TACE over MMP-1 and MMP-9. • How can the pharmaceutical industry increase the probability of technical success (p(TS))? What are the major causes of Phase II and III attrition?
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