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Descubrimiento de frmacos (drug discovery).

Dr. Cristina Murga


Departamento de Biologa Molecular-Centro de
Biologa Molecular Severo Ochoa
(UAM-CSIC)
cristina.murga@uam.es
URL: http://cmurga.cbmso.es/

0"

What is a medicinal drug?


A drug is an agent that causes a change
in the functionality of a defined
molecular target in a manner that has an
impact on the prevention, treatment or
cure of a disease.
Desirable characteristics:
- Effective while keeping selectivity for its target
- Active within acceptable safety margins
- Good bioavailability

CH3
N
CH3

! Low Molecular Weight molecules (small


molecules or New Chemical Entities,
NCE)
! Natural Products
! Synthetic Molecules
! Peptides and Antibodies
! Hormones, cytokines, (biologicals or
biopharmaceuticals)
! Oligonucleotides and siRNA
!

O
NH2

CH3
N
CH3

H3C

N
H3CO
H3CO

N
1"

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"

Drug Discovery Paradigms (i): Long and risky

Average:(10+15(years(per(drug"
4"

Paradigmas del descubrimiento de frmacos (ii): caro

Promedio:(1.000(mill($(/medicamento.(
5"

Vaccines(
4(%(

SyntheGc(
but(inspired(
in(Nat.(Prod.(
24(%(

N(=(1184(
Totally(
syntheGc(
30(%(

New trends and


paradoxes in DD&D
(drug discovery &
development)

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"

The keys to drug discovery and development:


Efficacy, Safety and Bioavailability
Efficacy / Potency

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"

Strategies for Target Identification


DRUG(TARGET:(Molecule"(protein,"DNA,"..)"able"to"recognize"a"drug"
and"produce"a"cellular"response"that"alters"the"course"of"a"disease."
#""Clinical(observaGons(
"V"Long"history"of"serendipitous"ndings"

"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"

! The target (protein, DNA, RNA,


) can be an essential point for
disease initiation, but also for
disease progression,
development or maintenance.
! Target validation approaches:
Pharmacological or siRNA
inhibition.
Over-expression studies.
Phenotype of the KO animal.
Expression in human tissues
(arrays, protein, tissue arrays,
laser capture microdissection).
-

11"

Technological Changes in Drug


Research!

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!

Adapted from Hugo Kubinyi !

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"

Hit (compuesto con la actividad farmacolgica deseada) "


Lead (Cabeza de serie) " Candidate (candidato a frmaco)

14"

"
"

Log([drug](

EFFICACY(

E.g.:(increase(in(cardiomyocyte(contracGon;(
amount(of(cell(death;(insulin((secreGon;(
membrane(depolarizaGon,(...(

How do we identify a hit?: Dose-response curves

Mean"ecacy"CONCENTRATION"

POTENCY(
15"

RESPONSE to drug
(% of maximal response
or % maximal inhibition)

EFFICACY (eficacia) of a drug


100"
"
"
"
"
50"
"
"
"
"
0"

[drug]=
EC50 or IC50

EFFICACY (= Emax) is the


MAXIMAL EFFECT obtained by
a drug in a given system (i.e.,
the response obtained at
saturating [drug]).

Maximal
Efficacy
=Emax

"
"
"

Drug"with"
lower"
ecacy"
(<Emax)"

Log([drug](

Emax defines the capacity of


each drug to reach its maximal
response (activating or inhibiting
a biological process)
independently of the
concentration of drug required
to obtain it (drug amount is
related to the potency of a
drug).

The EC50 ( efficacy CONCENTRATION 50%) is the concentration of a drug able to


provoke a half-maximal response of that system.
For INHIBITORY DRUGS (e.g. antagonist, enzyme inhibitors, ) the EC50 is usually called
IC50= concentration that provokes a half maximal inhibition. (see Supplementary Material).

The POTENCY of a drug describes the


amount (concentration) of drug that
promotes a given effect.

A compound is more potent than other


if the concentration required to reach
the mean effect is lower (the smaller
the EC50, the greater the potency).

A low potency becomes a problem


ONLY when the amount required to
reach the effective dose is toxic,
expensive or difficult to administer.

% ANALGESIC RESPONSE

Drug Potency: EC50

POTENCY correlates inversely with the


EC50 and is usually defined as 1/EC50 or
1/IC50.

Potency is used to compare competing


compounds: potency of the best one is
taken as a standard (Supplementary Material).

16

100"
"
"
"
"
50"
"
"
"
"
0"

1/EC50(A) =
POTENCY of A.

In cohort statistical studies (e.g., in patients) the EC50


is substituted by the ED50 ( efficacy DOSE 50%) :
dose of drug that provides the desired therapeutic
effect IN HALF OF THE POPULATION of individuals
(see Supplementary Material).

Emax =
EFFICACY

Log([drug](

$(EC50((or(IC50)=(%(Potency"

Potency"of"A"(hidromorne)">B(morne)">"C"(codeine)">"aspirin"

The best drugs are those with the higest


potency and efficacy possible: there might be
some with high potency but low efficacy and
viceversa.
17

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"

Strategies for the identification of hits and leads. !


1.Targeted or Focused screening (non-random): e.g. specific libraries, or extracts
from natural products (plants, animals) and traditional medicine with improved chance
of therapeutic effect: taxol, antibiotics, morphine, cocaine,

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.

3. Clinical observations: new activities found in trials with a different aim:

Viagra

(sildenafil citrate) was discovered in an anti-hypertensive study.

4. Random screening: explore every available compound: streptomycin, tetracyclin.


5. Rational approach:
-from molecules already having an activity of interest, e.g.:
- Neurotransmitters: Cimetidine H2-antagonist was developed as an antiulcer using histamine as a lead compound.
- Endogenous hormones: norgestel derives from progesterone.
-based on knowledge of the molecular basis of pathology: Gleevec (Imanitib) for BcrAbl, Herceptin (Trastuzumab) anti-HER2; Iressa (Gefinitib) for EGFRc.

19!

Natural product screening

Many bioactive natural products have


been identified by traditional medicine !
SyntheGc(
justification for systematic screening of
but(inspired(
plant and animal extracts.
in(Nat.(Prod.(
24(%(
the majority of the worlds population exclusively uses
drugs from natural sources
35% of marketed drugs contain principles of natural
origin
less than 5% out of 500,000 higher plant species
have been screened pharmacologically
each plant may contain 10,000 different
constituents.

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.

Selective Optimization of Side Activities

The most fruitful basis for the discovery


of a new drug is to start with an old drug
Sir James Black, Nobel Prize 1988!

La pruebas clnicas en fase II


no mostraron eficacia, se volvi
a fase I para incrementar la
dosis en voluntarios sanos.
stos reportaron una
prolongacin de la ereccin: se
descubri que la inhibicin de la
PDE5 (expresada en corpus
cavernosum) bloquea la
degradacin de cGMP, lo que
conlleva un continuo fujo de
sangre
Dramamina - testado como antihistamnico, se comercializa
como anti-nusea

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

Therapy for some important diseases, mostly


complex diseases (cardiovascular, cancer, ),
requires hitting multiple targets.
Instead of pursuing highly selective compounds for
unique targets, that is, single keys for specific
locks, the goal is shifting towards identifying ideal
master keys able to regulate a set of multiple
locks since the clinical benefit usually associated
complex biological processes.

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"""""""""""""""""""""

! Las curvas de inhibicin


nos muestran la eficacia
de un compuesto para
impedir un cierto efecto
biolgico.

IC50

Cul"de"estos"frmacos"Nene"un"efecto"inhibidor"
ms"potente?"Respuesta:"abajo"inverNda."
24

B es ms potente que C y ste ms que A

COMPARACION DE LOS EFECTOS ENTRE


FRMACOS: RAZN DE POTENCIAS.
- Comparaciones a una dosis concreta no resultan
cuantitativas, porque a diferentes dosis las diferencias
entre compuestos son distintas (ej., comparar A1 y A2).
- Se deben COMPARAR LAS DOSIS QUE CAUSAN EL
MISMO EFECTO (POTENCIAS) ya que a lo largo de
toda la sigmoide la relacin de la potencia de un
frmaco sobre la del otro es la misma (log M). Es lo que
se llama RAZN DE POTENCIAS (M, potency ratio).

Este tipo de comparaciones suele simplificarse


utilizando dosis en el tramo lineal de la sigmoide
( parallel line assays ). El ensayo ms simple es
el 2+2 (2 dosis de estndar y 2 de compuesto
en varios pacientes o animales).
En muchos casos este tipo de comparacin NO
es correcta (las lneas NO son paralelas) como
para frmacos con distintos mecanismos de
accin o ligandos con diferentes efectos
mximos (eficacias).
RANG 6ED PP90: FIG 6.3 & 6.4"

25

QUANTAL AND GRADED RESPONSES

- An assay may be based on a graded


response (e.g. change in blood glucose
concentration, contraction of a strip of
smooth muscle, heart rate), or on all-ornothing responses (e.g. 5-year survival or
death, sleep or not).
- Graded dose-response relationships
describe the effect of various doses of a
drug on 1 individual, whereas quantal
relationships show the frequency at which
various doses of a drug are effective on a
population of individuals.
- Usually, the % of animals or patients
responding to each dose and to those below
is plotted against increasing doses.

Golan / Levine s

- the distribution follows a NORMAL


(Gaussian) bell shaped curve around the
MEDIAN (ED50).

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."

ME TOO DRUGS: frmacos muy similares con


perfiles poco distintos a los originales: no suponen
un avance real excepto por motivos comerciales.
Dos de cada tres medicamentos aprobados en la
ltima dcada son versiones de frmacos existentes
ELMUNDOSALUD.COM MEDICINA

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"

ME BETTER DRUGS. Ej: Sucesivas


generaciones de penicilinas: ms activas,
disponibles via oral, espectro ms amplio,
eficaces contra cepas resistentes.!
H H

H
N

R
O

S
O

CH3
CH3

COOH
H
penicillin V (R = PhOCH2)
penicillin G (R = CH2 Ph)
2.2

28!

29"

Discovery of drugs by chance (serendipity)


Penicillin:( Penicillin happened, it came out of the blue. !
A. Fleming,1930"
H
"a"Petri"dish"was"contaminated"with"fungi"spores"(forgo|en"on"
NHCH 3
N
CH 2Cl
N
..
."
CH 3NH2
CH 2Cl
a"table"on"a"holiday"period")"
N+
N
O-

Cl

"weather"was"parNcularly"cold"

+ O-

Cl

"a"parNcular"strain"of"fungi"grew"which"was"a"good"ampicillin"
2.6
producer""
CH 3NH2
"Fleming"observed"that"bacteria"did"not"grow"in"the"
neighboring"areas"andDID"SOMETHING"ABOUT"IT!!" NHCH 3
N

Cl

CH 2NHCH 3

N+ O

Hugo Kubinyi!

Cl

.. CH 2 Cl
N
OH

Benzodiacepines: In 1955 Roche prepared a


series of potential tranquilizers.!
""
They could not find any compound with the
desired activity and the project was abandoned.!
In 1957, during a lab cleaning an untested vial
was found. It was shown to be highly active.!
It became the first benzodiacepine (Librium)!

Cl

NHCH 3. HCl
N+

O-

Librium!

chlordiazepoxide HCl
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!