Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Escursione storica
Drug discovery
Esempi farmaci moderni
Processo immissione nel mercato
Conclusioni
3000 a.c. Tavolette Sumere, indicazioni sulle operazioni galeniche, estratti acquosi o
oleosi. Nessuna indicazione sulle quantit, pesi, misure.
Tradizione orale ?
1550 a.c. papiro di Ebers, di Hearst, tutto rigorosamente misurato
estratti acquosi o oleosi. Medicamenti a base di birra, latte
vino.
600 a.c. Romani, pratica medica, influenzata dagli etruschi,
accompagnata da formule magiche e invocazioni alle divinit.
Casta sacerdotale era dedita alla Ars Divinatoria consiste nellinterpretazione di
segni e presagi offerti dalla natura
460 a.c. Ippocrate, ideatore della medicina razionale, distacco dalla figura
del medico-sacerdote. Inizio dellosservazione clinica obiettiva.
primum non nocere : il medico deve essere parco nella somministrazione dei
medicamenti
teoria medica dei quattro umori: sangue (cuore), flemma (cervello), bile (fegato),
atrabile (milza)
Armamentario:
elleboro nero, coloquintide, veratro bianco, oppio, belladonna, scilla
476-1492 d.c.
Il mantenimento del sapere in occidente affidato ai monasteri che
mantengono gli scritti di Galeno, Ippocrate, Plinio. Nasce lOrto dei Semplici e lArmarium
Pigmentarium (Spezeria del convento)
XV-XVII secolo
Philippus Aureolus Theophrastus Bombastus von Hohenheim detto
Paracelso, alchimista fondatore della iatrochimica il vero scopo della chimica non consiste
nella fabbricazione delloro, ma nella preparazione delle medicine
La malattia uno squilibrio chimico del corpo che pu essere ristabilito attraverso luso di
altre sostanze chimiche.
Scopre il Laudano
Nasce lattenzione verso il principio attivo del preparato farmaceutico
Comincia la rivoluzione scientifica: momento di rottura con la
tradizione medievale
Newton, Keplero, Galilei, Pascal, Boyle
anche in medicina e biologia:
scoperta di batteri e protozoi (Van Leeuwenhoek)
dimostrazione della falsit della generazione spontanea (Francesco
Redi): nessun organismo si genera spontaneamente, ma ognuno
nasce da altri esseri viventi della sua stessa specie
Pasteur dovette ridimostrare, un paio di secoli dopo, la falsit della teoria
XVIII secolo
Lavoisier pone le basi della chimica moderna introducendo il metodo
scientifico e la necessit di determinazioni quantitative e riproducibili
Nasce la chimica farmaceutica con Scheele con lidentificazione di molecole di interesse
biochimico e farmaceutico, Withering individua nelle foglie della digitale una sostanza con
propriet cardiotoniche
1775 Prieslty con il protossido di azoto gas ad azione esilalarante ed anestetica, che viene
ripreso il secolo successivo dal dentista Wells che per non ebbe seguito.
1846 Morton, amico e collega di Wells nonch studente, fece una
dimostrazione utilizzando etere per lasportazione di un tumore
mandibolare
Nasce lanestesia in camera operatoria
XIX secolo
Comincia il boom della chimica farmaceutica grazie allisolamento e la
purificazione dalle piante medicinali dei principi attivi
Inizia un processo di ricerca e produzione di nuove molecole su vasta scala, nascono i legami con
la botanica, microbiologia, farmacologia
Vengono definiti gli alcaloidi, molecole con caratteristiche basiche presenti nelle piante
medicinali
Vengono isolati in rapida successione morfina, emetina, stricinina, atropina, caffeina, chinina,
codeina etc
Passaggio da preparati galenici classici, parzialmente efficaci e spesso tossici, a forme
farmaceutiche rigorose capaci di provocare un effetto costante e riproducibile
Nascono le aziende farmaceutiche
Drug definition
Lead compund
LEADS
Pharmaceutical chemists do not synthesise compounds at random. They usually
start with a so-called lead compound (ie a compound which leads them
onward), and make and test compounds with structures closely related to it.
This lead compound will have shown some activity as a drug and the chemists
hope that they can find a derivative of it which is better is more effective as a
drug, has fewer side effects, is cheaper to make etc.
A good example of the lead compound approach is the development of the drug
aspirin:
John Langley in 1905 he proposed that so called receptive substances in the body could
accept either a stimulating compound, which would cause a biological response, or a
non-stimulating compound, which would prevent a biological response.
It is now universally accepted that the binding of a chemical agent, referred to as a
ligand, to a so called receptor sets in motion a series of biochemical events that result in
a biological or pharmacological effect: concept of drug molecolar target
Furthermore, a drug is most effective when all or a significant part of its molecular shape
and electron distribution (stereoelectronic structure), is complementary with the
stereoelectronic structure of the receptor responsible for the desired biological action.
The section of the structure of a ligand that binds to a receptor is known as its
pharmacophore.
It is now believed that side effects can arise when the drug binds to either the receptor
responsible for the desired biological response or to different receptors.
Drug Design
Me-too drugs
The cost of introducing a new drug to the market is extremely high and continues to
escalate. One has to be very sure that a new drug is going to be profitable before it is
placed on the market. Consequently, the board of directors decision to market a drug
or not depends largely on information supplied by the accountancy department rather
than ethical and medical considerations.
One way of cutting costs is for companies to produce drugs with similar activities and
molecular structures to their competitors. These drugs are known as the me-too
drugs.
Chain and Floreys choice turned out to be very fortunate. Because of its efficacy and
lack of toxicity, penicillin made the most compelling case for antibiotics in general
Binding affinity
Efficacy
Specificity
Toxicity
Lead identification
Generally speaking, first-pass HTS assays (the primary screen) are less quantitative than
traditional biological assays. Often, compounds are only tested in duplicate (an
increasing number of companies are using singlets), and usually at one concentration
(most often in the 110 M range for combinatorial chemistry libraries). If a hit
(positive) is discovered, more accurate secondary assays are used for elucidating the
biological role and dose-response curve calculation.
Analogues are made of the most promising of these compounds and they in turn are
subjected to the screening procedure. This sequence of selective screening and
synthesis of analogues may be repeated many times before a potentially useful drug is
found.
Drug Design
The design cycle describes the optimization of a lead strucutre to one or several
development candidates. It is and iterative process with evolutionary character
Sources of drugs
Once the ability to screen libraries developed, the pressure on medicinal chemists
increased to generate large quantities of compounds for screening.
It originally started with drugs and lead compounds derived from natural sources, such
as animals, plants, trees and microorganisms. Marine sources were not utilized to any
extent until the mid-20th century.
Today, natural sources are still important, but the majority of lead compounds are
synthesized in the laboratory. The nature of these synthetic compounds is initially
decided from a consideration of the biochemistry of the pathogenic condition.
Natural sources
Natural sources are still important sources of lead compounds and new drugs.
However, the large diversity of potential natural sources in the world makes the
technique of random screening a highly empirical process.
The screening of local folk remedies (ethnopharmacology) offers the basis of a more
systematic approach
potent neurotoxin
its primary
therapeutic use is in
the treatment of
gout
Lead compounds
Antibiotic
derived from the actinobacterium
Streptomyces griseus.
cholecistokinin
Natural sources
Anticancer agent
Lead compounds
Rational design
The market
For the first time in decades, the oncology therapeutic area has overtaken cardiovascular
medicine as the leading revenue contributor
A major reason for the rise of oncology as a revenue contributor comes from the success of
bevacizumab (Avastin), rituximab (Mabthera/ Rituxan) and trastuzumab (Herceptin) and of
imatinib (Glivec/Gleevec)
Rational design
GLEEVEC case
Chronic Myeloid Leukemia (CML)
The Philadelphia (Ph) chromosome is an abbreviated chromosome 22 that was shortchanged
in an a reciprocal exchange of material with chromosome 9.
This translocation occurs in a cell in the bonemarrow cell and causes CML
On a molecular level the Philadelphia
chromosome translocation results in the
production of a fusion protein.
A large portion of a proto-oncogene, called
ABL, on chromosome 9 is translocated to the
BCR gene on chromosome 22.
The two gene segments are fused and
ultimately produce a chimeric protein that is
larger than the normal ABL protein.
The clinical development was particularly rapid, as can be seen by comparison with the
typical drug discovery and development times shown in the inset. An NDA for Glivec was
submitted just two years and nine months after treatment of the first patient with CML,
and FDA approval was given less than three months after application. CML, chronic
myelogenous leukaemia; GIST, gastrointestinal stromal tumour; NDA, new drug application;
PKC, protein kinase C.
Monoclonal antibodies:
Molecular biomedical research identifies potential drug target
EGFR and VEGFR signaling share common pathways. The network of both family receptors may
control pathways that affect cell proliferation, survival, differentiation, and migration.
Antibodies
Complex protein-based molecules produced by B lymphocytes that bind to and help to
eliminate foreign and infectious agents in the body.
Antibodies are Y shaped, having two sets of branches attached to a single stem.
The arms of the Y (Fab) are the so called variable regions, the tips of the arms contain
antigen-binding regions, and the stem (Fc) is a constant region.
The constant regions trigger effector functions (phagocytosis, cytolysis) by linking the
complex to other cells of the immune system.
Monoclonal antibodies (mAbs) can be designed to selectively target tumour cells and elicit a
variety of responses once bound.
206 therapeutic oncology mAbs entered clinical study sponsored by commercial organizations
between January 1980 and December 2005 (8.24/year).
To date, 12 of these anticancer mAbs have been approved for marketing in at least one
country
The success of mAbs is due to the rapid identification of new molecolar targets and to the
improvement of biotechnological methods for the production
Originally, mAbs were antibodies produced from a single B lymphocyte. mAbs of a defined
peptide sequence have identical antigen-binding regions and bind to the same site (the
epitope) of an antigen.
Modes of action
Conjugated mAbs can increase the specificity of chemo- or radiation therapy and improve
the efficacy of immunotherapy, but have some drawbacks; they are more difficult to
manufacture and may have greater safety issues compared with their naked counterparts.
Unconjugated mAbs can function through more than one mechanism, but a common primary
mode of action is the destruction of targeted cells through activation of components of the
human immune system.
For example, after binding to a target, mAbs can recruit effector cells such as natural killer cells
or macrophages to destroy the target
Although all eight currently approved unmodified anticancer mAbs potentially have the ability
to function through activation of the immune system, only two rituximab (Rituxan; Biogen
Idec) and alemtuzumab (Campath; Genzyme) are believed to use this way as their primary
mode of action.
The other six products function through alternative primary modes of action (blockade of
growth factorreceptor interaction, receptor downmodulation and inhibition of signalling).
mAbs are not necessarily restricted to a single mode of action.
For example, trastuzumab (Herceptin; Genentech) has been reported to induce immune system
modulation as a possible alternative or additional mechanism to human epidermal growth
factor receptor 2 (HER2) downmodulation
Efficacy
The use of monoclonal antibodies is diffuse in cancer therapy
Clinical responses varies from 15-50% of patients treated in clinical trials (partial or full
response).
Some MAbs have increased the efficacy of treatment of certain tumors, with acceptable safety
profiles.
Issues to be addressed include dosing strategies, timing, and schedule of antibody
administration; duration of treatment; need for tailoring; and further testing under specific
circumstances.
The discovery of effective combinations with other biologic agents would be very useful.
Multimodality approaches, based on synergistic effects observed with the combination of
antibodies with chemotherapeutic drugs and/or radiotherapy also merit further investigation
Tumor initiation
Drug development
1 Drug
Molecule
patentable
nonnon-teratogenic
10,000 Drug
Candidates
Valid
Biomedical
Hypothesis?
Statistics show that out of each 10,000 or so new molecules generated, only about one will ultimately survive
the array of requirements necessary for a candidate molecule to become a drug that reaches patients
1 Drug
Launch
CostCost-effective manufacturing
Carcinogenicity studies
10 Drug
Molecules
Identify disease
Isolate protein
involved in
disease (2-5 years)
Preclinical testing
(1-3 years)
Formulation
FDA approval
(2-3 years)
The principle of the magic bullet itself or, as we would say today, the
concept of exclusivity in which a drug interacts with only one target
at least in some multifactorial diseases, a drug with multiple wellchosen points of attack might be preferable to a drug with only one
target, even if that target is crucial and its engagement by the drug in
question absolutely specific
Some authors have therefore advocated a return to biology-driven
strategies that expose drug candidates to more complex test systems
Approaches of this type might indeed help to select compounds that
address a typical combination of targets, rather than a single molecular
entity the so called magic bullets of the second order
Bibliografia:
Per la parte storico-introduttiva:
Il progresso terapeutico di Colapinto Leonardo, Annetta Antonino, Aboca Edizioni
Per la parte scientifica:
Renaud Capdeville, Elisabeth Buchdunger, Juerg Zimmermann and Alex Matter, NATURE REVIEWS | DRUG
DISCOVERY, JULY 2002 | 493
Jeffrey M. Rosen1 and Craig T. Jordan2, 26 JUNE 2009 VOL 324 SCIENCE, 1670
Janice M. Reichert and Viia E. Valge-Archer, NATURE REVIEWS | DRUG DISCOVERY, VOLUME 6 | MAY 2007 |
349
Jrgen Drews, NATURE REVIEWS | DRUG DISCOVERY, VOLUME 5 | AUGUST 2006 | 635
2008 FDA drug approvals, NATURE REVIEWS | Drug Discovery, VOLUME 8 | FEBRUARY 2009 | 93
David J. Newman* and Gordon M. Cragg, J. Nat. Prod. 2007, 70, 461-477
Sales trends by therapeutic area: 20082013, nature reviews | Drug DiscovEry, volume 8 | september 2009
| 689
Sales of biologics to show robust growth through to 2013 nature reviews | Drug DiscovEry, volume 8 |
november 2009 | 837
Bin-Bing S. Zhou*, Haiying Zhang, Marc Damelin*, Kenneth G. Geles*,
Justin C. Grindley* and Peter B. Dirks, nature reviews | Drug DiscovEry 806 | ocTober 2009 | VoluMe 8