Professional Documents
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Descubrimiento de frmacos
drug discovery
El proceso de
descubrimiento y
Desarrollo de frmacos
drug development
desarrollo de frmacos
Estudios preclnicos
preclinical studies
Fases clnicas
clinical trials
2"
From Ehrlichs
magic bullets
to modern
drug
discovery.
"Federico"Gago,"UAH"
3"
Average:(10+15(years(per(drug"
4"
Promedio:(1.000(mill($(/medicamento.(
5"
Vaccines(
4(%(
SyntheGc(
but(inspired(
in(Nat.(Prod.(
24(%(
N(=(1184(
Totally(
syntheGc(
30(%(
Biologicals((NBE)(
14(%(
Natural(Products(
5(%(
SemisyntheGc(
(derived(from(Nat.(Prod.)(
23(%(
Newman"&"Cragg"(2007)"J.Nat.Prod."70:461"
Munos"B"(2009)"Nat"Rev"Drug"Disc"8,"959V68"
Small"molecules"(NCEs)"
BiopharmaceuNcals"(NBEs)"
Total"
2008"
2006"
2004"
2002"
2000"
1998"
1996"
1994"
1992"
1990"
1988"
1986"
1984"
1982"
1980"
1978"
1976"
1974"
1972"
1970"
1968"
1966"
1964"
1962"
1960"
1958"
1956"
1954"
1952"
1950"
Number"of"NCEs"or"NBEs"
NCEs:"new"chemical"enNNes"
NBEs:"new"biological"enNNes"
Therapeutic window
eg: ED50 / MTD
Safety
Appropriate
drug delivery and
biodistribution
Safe dose to
prevent toxicity
Bioavailability
7"
6"
Modern(Drug(Discovery:(Key(stages(
"(
1. SelecNon"of"a"project"(choosing"a"disease)"
Choose(a(disease(
Choose(a(drug(target(
2. IdenNcaNon"of"a"drug"target""
3. Target"validaNon""
Validate(the(target(
4. Development"of"a"reliable"robust"bioassay"
Design(an(assay(for(hit/
5. IdenNcaNon"of"hits"
lead(idenGcaGon(
6. SelecNon"and"opNmizaNon"of"the"lead"(H2L)"""
IdenNcaNon"of"hits"
""usually"PATENT(APPLICATION((FILING)(
7. Development"of"the"lead(s)"into"a"drug"candidate"(L2C)" Hit"to"lead"
8. Preclinical"tesNng"(if"not"performed"before)"
Lead"to"candidate""
9. Clinical"trials"(humans)"a`er"corresponding"permit:"
""invesGgaGonal(new(drug(applicaGon((IND)(
Preclinical"tesNng"
10. MarkeNng"of"the"drug:""
Clinical"trials"
"MAA:(MarkeGng(AuthorisaGon(ApplicaGon((UE)/(
MarkeNng"of"the"drug"
NDA:(New(Drug(ApplicaGon((US)("
and"surveillance"
11. PostVmarkeNng"surveillance"
"
"
"
8"
TOTAL:"10V15"years,"US$"1,000"mil."
Programme(selecGon(
(
"1900s""many"therapeuNc"opportuniNes"(infecNous,"cardiovascular"
diseases,"...)"
"2000s""therapies"available"for"many"condiNons"+"increased"
regulatory"safety"protocols"""
"novel"agents"must"not"only"be"clinically"eecNve"but"also"have"
clear"advantages"over"exisNng"therapies."
SNll,"many"diseases"present"an"area"of"unmet"medical"needs"(AD,"
cancer,()"
Choose(a(disease(
Choose(a(drug(target(
Validate(the(target(
Design(an(assay(for(hit/lead(
idenGcaGon(
IdenNcaNon"of"hits"
COMPANIES(TAKE(INTO(ACCOUNT:((
A)"the"medical(need"
"life"threatening?"/"Non"lifeVthreatening"but"very"frequent?"
COMPARE:((
B)"availability"of"current(therapy:"
"is"level"of"saNsfacNon"high"or"low?/""new"drug"resulNng"in"
parNcular"advantage"to"the"paNent?"
C)"compeGtor(acGvity:"Will"the"new"drug"
"
"present"a"novel"therapeuNc"mechanism"(new"family"of"
drugs)?/""permit"a"novel"approach"to"the"management"of"
the"disease?"
D)"commercial(opportunity:"
Alzheimers(
disease((US$(
330(billions)(
vs(Malaria(
(US$(2(
billions)(
Depression(
(112(million(
people)(vs(
Beta+
thalassemia(
(1(in(10,000)(
"potenNal"market"(number"of"paNents,"market,)/"
"duraNon"of"proposed"therapy"(chronic,"acute,)"
9"
"V"OVlabel"prescripNons"(frmacos)usados)para)terapias)diferentes)a)las)recetadas))
"V"Clinical"invesNgaNon"of"combinaNon"therapies"
"V"Adv.:"observaNon"in"humans"&"short"development"Nmes"
"V"Disadv.:"use"patent"may"not"prove"strong"
#""Increasing(disease(knowledge""
"V"ScienNc"literature"&"databases.""
Choose(a(disease(
Choose(a(drug(target(
Validate(the(target(
Design(an(assay(for(hit/
lead(idenGcaGon(
IdenNcaNon"of"hits"
"V"liaison"with"academic"groups"and"startVup"companies"
"V"Adv:"provide"genuine"innovaNon"
"V"Disadv:"knowledge"may"be"common"knowledge"
#((Genomics/Proteomics/Metabolomics:"gene"or"protein"expression/
funcNon"in"health"and"disease""
"V"Allowed"by"strong"bioinformaNcs""
"V"Adv:"high"innovaNon"&"compeNNve"edge"
"V"Disadv:"high"risk"&"long"term"
#((Pharmacogenomics"(study"of"populaNons"responses"to"drug"treatments)"
PharmacogeneGcs((geneNc"idenNcaNon"of"high"responders"or"high"risk"paNents)"
"V"Adv:"adds"value"to"treatment"and"reduces"healthcare"cost"
"V"Adv:"high"innovaNon"&"compeNNve"edge"
"V"Disadv:"high"risk"&"long"term"
"V"Future:"gene"chips"to"dene"paNent"genome""V"personalized(medicine(
Target Validation
! Many of the drug discovery
projects fail due to poor Target
Validation: a biomolecule may be
involved in the disease
process, but to be a drug target
it has to be validated = shown
to be critical for the disease
progress or symptoms.
10"
Choose(a(disease(
Choose(a(drug(target(
Validate(the(target(
Design(an(assay(for(
hit/lead(idenGcaGon(
IdenNcaNon"of"hits"
11"
Up to the 70s!
Chemistry and hypotheses guide the syntheses!
Bottleneck: Animal experiments, isolated organs!
Up to the 90s!
Molecular Modelling!
In vitro models (enzyme inhibition, receptor binding)!
Bottleneck: Dedicated syntheses of drugs!
Up to the year 2000:!
Gene technology (production of proteins)!
Combinatorial chemistry (mixtures, chemistry-driven)!
Structure-based design of ligands!
High-throughput test models (HTS)!
Bottleneck: ADMET properties!
Today:!
Genomics, proteomics and bioinformatics!
Transgenic animals for proof of concept!
Combinatorial chemistry!
(single compounds, design-driven)!
Structure-based and computer-aided design!
of ligands!
Ultra-high-throughput test models (u-HTS)!
Data mining!
Virtual screening!
ADMET profiles (HTS and in silico)!
Bottleneck: Target validation, drugable
targets!
!
12!
Modern(Drug(Discovery:(Key(stages(
" (
"In(class(
1. SelecNon"of"a"project"(choosing"a"disease)"
Choose(a(disease(
acGvity:(
Choose(a(drug(target(
2. IdenNcaNon"of"a"drug"target""
project(
3. Target"validaNon""
design.((
Validate(the(target(
4. Development"of"a"reliable"robust"bioassay"
Design(an(assay(for(hit/
5. IdenNcaNon"of"hits"
lead(idenGcaGon(
6. SelecNon"and"opNmizaNon"of"the"lead"(H2L)"""
IdenNcaNon"of"hits"
""usually"PATENT(APPLICATION((FILING)(
7. Development"of"the"lead(s)"into"a"drug"candidate" Hit"to"lead"
8. Preclinical"tesNng"(if"not"performed"before)"
Lead"to"candidate""
9. Clinical"trials"(humans)"a`er"corresponding"permit:"
""invesGgaGonal(new(drug(applicaGon((IND)(
Preclinical"tesNng"
10. MarkeNng"of"the"drug"""
Clinical"trials"
"MAA:(MarkeGng(AuthorisaGon(ApplicaGon((UE)/(
MarkeNng"of"the"drug"
NDA:(New(Drug(ApplicaGon((US)("
and"surveillance"
11. PostVmarkeNng"surveillance"
13"
14"
"
"
Log([drug](
EFFICACY(
E.g.:(increase(in(cardiomyocyte(contracGon;(
amount(of(cell(death;(insulin((secreGon;(
membrane(depolarizaGon,(...(
Mean"ecacy"CONCENTRATION"
POTENCY(
15"
RESPONSE to drug
(% of maximal response
or % maximal inhibition)
[drug]=
EC50 or IC50
Maximal
Efficacy
=Emax
"
"
"
Drug"with"
lower"
ecacy"
(<Emax)"
Log([drug](
% ANALGESIC RESPONSE
16
100"
"
"
"
"
50"
"
"
"
"
0"
1/EC50(A) =
POTENCY of A.
Emax =
EFFICACY
Log([drug](
$(EC50((or(IC50)=(%(Potency"
Potency"of"A"(hidromorne)">B(morne)">"C"(codeine)">"aspirin"
ACTIVIDADES:(
(
1.V"OBLIGATORIA:"HACER"
Y"ENVIAR"EL"
CUESTIONARIO"SOBRE"
DESCUBRIMIENTO"DE"
FRMACOS"EN"
MOODLE."Abierto"desde"
21/1"@11:40h"hasta"el"
27/1"a"las"23:55."Mximo"
2"intentos,"SIN"
penalizacin."
"
2.V"ACTIVIDAD"EN"AULA"
(Semana"prxima):"
DISEO"DE"UN"
PROYECTO"(ELECCIN"DE"
UNA"ENFERMENDAD"+"
UNA"DIANA"
TERAPUTICA)"Y"
SELECCIN"DE"UN"
BIOENSAYO"ADECUADO."
18"
2. Metabolite analysis: by-products of drug metabolism in the body are analyzed for the
same activity or for alternative ones: Terfenadine hydrocloride (Seldane) is a potent antihistaminic but can cause abnormal cardiac rhythm, however its product fenoxfenadine hydrocloride
(Allegra) does not have that problem.
Viagra
19!
Vaccines(
4(%( Biologicals((NBE)(
14(%(
Natural(
Products(5(%(
TOTAL(
52(%(
N(=(1184(
Totally(
SyntheGc(30(%(
SemisyntheGc(
(derived(from(Nat.(Prod.)(
23(%(
Newman"&"Cragg"(2007)"J.Nat.Prod."70:461"
Disadvantages:
active component frequently scarce"
problematic isolation
structures often complex" difficulty to
identify the pharmacophore and synthesize it
extracts often contain other molecules that
can hide or quench biological activity"
Advantages:
complex structures with
many substituents = greater
success in engaging targets"
20"
Descubrimiento de frmacos a
partir de observaciones clnicas
Viagra (citrato de sildenafilo)
se analiz como un antihipertensivo/antiangina de
pecho.
21!
SUPPLEMENTARY"
INFORMATION"
22"
Shiking(paradigms:(from(!
single(to(mulG+target(
approaches(
!
Shi`ing"from"the"single"to"the"mulNtarget"paradigm"
in"drug"discovery"Jose"L."MedinaVFranco"et"al."Drug
Discovery Today Volume 18, Numbers 9/10 May 2013
Chemogenomics:(emerging"eld"that"aims"to"systemaNcally"idenNfy"all"
possible"ligands"for"all"possible"targets"including"predicNon"of"the"
polypharmacological"prole"of"bioacNve"compounds"
"
23"
! La IC50 (inhibitory
concentration o
concentracin
inhibitoria media CI50-) es la
concentracin a la que
se consigue el la mitad
del efecto inhibitorio
mximo.
! La IC50 es proporcional
a la Ki (Kd del inhibidor
por su diana)
IC50"
Respuesta"""""""""""""""""""""
IC50
Cul"de"estos"frmacos"Nene"un"efecto"inhibidor"
ms"potente?"Respuesta:"abajo"inverNda."
24
25
Golan / Levine s
Quantal dose-response relationships are used for predicting the effects of a drug when it is administered
to a population of individuals, and for determining population-based toxic doses and lethal doses.
These doses are called the ED50 (dose at which 50% of subjects exhibit a given therapeutic response to a
drug), TD50 (dose at which 50% of subjects experience a given toxic response), and LD50 (dose at which
50% of subjects die).
Note that ED50 is the dose at which 50% of subjects respond to a drug, while EC50 (as described
before) is the dose at which a drug elicits a half-maximal effect in an individual subject.
26
There(are(three(major(components(of(target(validaGon(using(human(
data:(Gssue(expression,(geneGcs,(and(clinical(experience.((
AcceleraNng"TherapeuNc"Development"for"Nervous"System"Disorders"
27"
Toward"FirstVinVHuman"Trials:"A"Workshop."April"8"and"9,"2013"
Copyright""NaNonal"Academy"of"Sciences."All"rights"reserved."
Pocos frmacos realmente nuevos. Segn un estudio que recoge 'The New York
Times', slo el 15% de los medicamentos aprobados en EEUU durante la ltima
dcada presentaba ventajas con respecto a los existentes. Adems, dos tercios
de los nuevos productos eran versiones modificadas o, incluso, idnticas a otros
que ya estaban en el mercado.
Por ejemplo, Sarafem , un medicamento para tratar el sndrome premenstrual,
no es ms que Prozac (el principio activo es el mismo, y la compaa que los
fabrica, tambin) pero con otro envase. Asimismo, Clarinex es una
reformulacin de Claritin (ambos para las alergias) y Nexium (para la lcera) lo
es de Prilosec.
Segn este informe, realizado por Nancy Chockley, presidenta de la fundacin
National Institute for Health Care Management , algunos de estos frmacos
reformulados se encuentran entre los ms anunciados. Adems, el aumento del
gasto en farmacutico (en medicamentos de prescripcin) se debe,
fundamentalmente, a estos productos que segn la FDA la agencia del
medicamento estadounidense no proporcionaban beneficios significativos con
respecto a preparados que ya estaban en el mercado.
Escasas novedades
Hasta ahora, ya se saba que muchos de los medicamentos aprobados eran
similares a otros existentes, pero el nuevo trabajo es el primero en emplear los
datos de la agencia federal para evaluar la presencia de estos productos. De
este modo se ha constatado que de los 1.035 frmacos aprobados por la
FDA entre 1989 y 2000, slo 361 (el 35%) contenan nuevos principios
activos. El resto tena compuestos que ya estaban presentes en otros
medicamentos disponibles. Asimismo, de entre estos 361 productos, la FDA
slo dio revisiones prioritarias a menos de la mitad. Estas revisiones se realizan
con frmacos que se consideran ms eficaces, con menos efectos secundarios o
que funcionan mejor que los preparados existentes.
A partir de estos datos el trabajo seala que slo el 15% de los frmacos
aprobados puede considerarse innovador, es decir, que contienen
principios activos que ofrecen una significativa mejora sobre los preparados
que ya estaban en el mercado.
Polmica
El presidente de PhRMA (la organizacin que agrupa a las principales
farmacuticas de EEUU) precisa que, aunque un medicamento sea parecido a
otro que ya est en el mercado, an puede ofrecer muchos beneficios al
paciente. Sin embargo, el estudio seala que las compaas confan cada
vez ms en estas versiones modificadas al ver que las patentes de sus
productos ms vendidos estn a punto de finalizar, tal y como ha
sucedido con Prozac, Claritin y Prilosec. Los medicamentos
'remodelados' aade la investigacin proporcionan elevados
ingresos, ya que desarrollarlos es mucho ms barato y rpido que
trabajar en un nuevo frmaco. Segn Chockley, esta es una evidencia ms
de que las compaas farmacuticas se estn conviertiendo en empresas de
mrketing
"Federico"Gago,"UAH"
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2.3
Serendipity: Sir Horace Walpole,
1754!
As Their Highnesses [re: the Princes of Serendip]!
travelled, they were always making discoveries, by
accidents and sagacity, of things which they were not in
quest of.!
Louis Pasteur, 1854!
Dans les champs de l observation, le hasard ne favorise
que les esprits prpars.!
Albert Szent-Gyrgi (1893-1986)!
Discovery consists of seeing what everybody else has
!
seen and thinking what nobody else has thought.!
30!