Transcript introduction – what is parkinson`s disease?

How are
medicines
developed?
What is it?
What’s inside?
What is inside a medicine?
Active ingredient
It looks for the
therapeutic target to
have an effect and cure
the disease
Therapeutic target
Active ingredient
It looks for the
therapeutic target to
have an effect and cure
the disease
Therapeutic target
How are medicines developed?
DEVELOPMENT SEQUENCE IN THE SEARCH FOR A MEDICINE
The search for a medicine is a long (10-25 years),
complex and expensive process consisting of several
stages.
DRUG
R&D
(2-10 years)
PRECLINICAL
STUDIES
(2-6 years)
In vitro/In vivo
CLINICAL DEVELOPMENT
PHASE I  PHASE II  PHASE III
Launch
of the
drug
PHASE IV
HOW IS A DRUG CANDIDATE DISCOVERED?
• A drug candidate can be discovered in different
ways:
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HOW IS A DRUG CANDIDATE DISCOVERED?
A drug candidate can be discovered in different ways:
Serendipity
chance
Chemical modification
Massive screening
Rational design
WE NOW HAVE A DRUG CANDIDATE!
PRECLINICAL DEVELOPMENT
• A thorough and complete preclinical study is required
before we can test a drug in humans:
• These preclinical studies include:
– Stability and toxicity studies
©Parc Científic Barcelona. Author: J. Planagumà
– In-vitro tests (proteins, cells, tissues and organs)
– In-vivo tests (animals)
CLINICAL DEVELOPMENT
• Clinical development is the longest and most costly part of
the search for new medicines. It consists of three phases:
PHASE I
Healthy volunteers
Safety and
dose
PHASE II
Patients
(100-300)
(drug or placebo)
Efficacy and
side
effects
PHASE III
Patients
(1300-3000)
Long-term
effects
AND FINALLY… THE DRUG IS LAUNCHED ON THE MARKET!
• If the drug has successfully passed the three clinical
phases, it is launched on the market, but the study
continues (Phase IV)
PHASE III
PHASE II
PHASE I
PHASE IV
SEARCH for DRUGS for
PARKINSON’S DISEASE
The Barcelona Science Park
research project
INTRODUCTION – WHAT IS PARKINSON’S DISEASE?
• Parkinson’s disease (PD) is a chronic and progressive
movement disorder characterised by:
– Coordination problems
– Slowed movements
– Generalised tremor
• It is the second most common neurodegenerative
disease and affects 1-2% of people over 60. There are
currently more than 4 million people suffering from PD
worldwide.
INTRODUCTION – PARKINSON’S DISEASE, CAUSES
• Our brain is our body’s control centre
and the cells responsible for it are
called neurons. These cells selfregenerate very slowly.
• Neurotransmitters are special chemical
compounds that enable neurones to
“talk to each other” and communicate.
INTRODUCTION – PARKINSON’S DISEASE, CAUSES
• We still do not know what causes
Parkinson’s disease, but we do know that
it is due to the loss or incorrect
functioning of the neurons responsible for
producing dopamine, a neurotransmitter.
• Dopamine
 Control of movement
• Dopamine is responsible for transmitting the signals required to
control
the movement
of our
muscles.in the control
Low dopamine
levels 
Difficulties
of movement
• A dopamine deficiency therefore leads to an imbalance in neuronal
transmission, preventing neurons from communicating properly. This
leads to a loss of motor function.
INTRODUCTION – PARKINSON’S DISEASE, TREATMENT
• The way to treat the disease’s progression
is by taking oral medicines.
tyrosine
L-dopa
dopamine
vesicles with the
dopamine transmitter
synapse
• The most commonly used medicine
today is levodopa, or L-dopa, which
consists of a chemical compound
that the brain uses to produce
dopamine.
dopamine
receptor
receptor cell
INTRODUCTION – PARKINSON’S DISEASE, TREATMENT
• Other medicines, which imitate the effect of
dopamine in the brain, are also used.
– e.g. bromocriptine, lisuride, pergolide, ropinirole, etc.
dopamine
imitator
receptor
receptor
Cell
membrane
Cell
membrane
Cell response
Cell response
INTRODUCTION – PARKINSON’S DISEASE, TREATMENT
• Unfortunately, these medicines have a large number of
side effects:
– Appearance of involuntary movements and tics
– Depression
– Hallucinations
• These medicines also cease to be effective with time.
• We need to produce new medicines with less side effects that
are active for longer periods.
RESEARCH, SYNTHESIS OF DRUGS FOR THE TREATMENT
OF PARKINSON’S DISEASE
• In the Barcelona Science Park, on the
Combinatory Chemistry Platform, scientists
are working on the synthesis of new
compounds that can be used as therapeutic
agents
in
the
treatment
of
neurodegenerative diseases such as
Parkinson’s or Schizophrenia that are:
– More active
– Less toxic
RESEARCH, SYNTHESIS OF DRUGS FOR THE TREATMENT
OF PARKINSON’S DISEASE
• A drug cocktail is currently administered to increase
the efficacy of these anti-Parkinson’s agents.
• The objective is to synthesise new molecules that are
more effective or have less side effects.
A
Anti-Parkinson’s agents
Drug cocktail
A single drug
D
RESEARCH, SYNTHESIS OF DRUGS FOR THE TREATMENT
OF PARKINSON’S DISEASE
New drug
Cell response
RESEARCH, DESIGN AND SYNTHESIS OF NEW MOLECULES
A
D
OH
O
O
O
N
NH
A
O
N
N
D
N
OH
XAC-COOH
(±)-PPHT
NH2
HOW DO WE SYNTHESISE THESE NEW MOLECULES IN THE
LAB?
O
O
CN
N
H
N
H
N
O
2 h, 80 ºC
O
NaOH 70%
pH 10-11
N
Ac2O
O
N
NH
+
NH2
96%
96%
NaNO2
CN
HOOC
AcOH
O
N
O
Na2S2O4
O
NH2
N
EtOAc/H2O
NH2
N
O
NO
N
NH2
76%
OHC
OH
I
+
75%
K2CO3
OHC
COOH
DMF, 60ºC
3 dias
O
COOH
reflujo en EtOH
62%
O
O
COOH
N
N
O
O
N
N
H
DIAD
N
O
N
N
NH2
75%
O
80%
COOH
HOW DO WE SYNTHESISE THESE NEW MOLECULES
IN THE LAB?
O
O
CN
N
H
N
H
N
O
2 h, 80 ºC
O
NaOH 70%
pH 10-11
N
Ac2O
O
N
NH
+
NH2
96%
96%
NaNO2
CN
HOOC
AcOH
O
N
O
Na2S2O4
O
NH2
N
EtOAc/H2O
NH2
N
O
NO
N
NH2
76%
OHC
OH
I
+
75%
K2CO3
OHC
COOH
DMF, 60ºC
3 days
dias
O
COOH
reflujoinenEtOH
EtOH
reflux
62%
O
O
COOH
N
N
O
O
N
N
H
DIAD
N
O
N
N
NH2
75%
O
80%
COOH
27
HOW DO WE SYNTHESISE THESE NEW MOLECULES
IN THE LAB?
O
O
CN
N
H
N
H
N
NaOH 70%
pH 10-11
N
1. Chemical reaction
Ac2O
O
2 h, 80 ºC
O
O
N
NH
+
NH2
96%
96%
NaNO2
CN
HOOC
AcOH
O
N
O
Na2S2O4
O
NH2
N
EtOAc/H2O
NH2
N
O
NO
N
NH2
76%
OHC
OH
I
+
75%
K2CO3
OHC
COOH
DMF, 60ºC
3 dias
O
COOH
reflujo en EtOH
62%
O
O
COOH
N
N
O
O
N
N
H
DIAD
N
O
N
N
NH2
75%
O
80%
COOH
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HOW DO WE SYNTHESISE THESE NEW MOLECULES
IN THE LAB?
2. Isolation and purification of the product
3. Characterisation of the product
WHAT ARE WE
GOING TO DO
TODAY?
HOW DO WE SYNTHESISE THESE NEW MOLECULES IN
THE LAB?
O
O
CN
N
H
N
H
N
O
2 h, 80 ºC
O
O
N
NH
+
NH2
96%
96%
CN
HOOC
NaOH 70%
pH 10-11
N
Ac2O
NaNO2
Chemical reaction
AcOH
O
N
O
Na2S2O4
O
NH2
N
EtOAc/H2O
NH2
N
O
NO
N
NH2
76%
OHC
OH
I
+
75%
K2CO3
OHC
COOH
DMF, 60ºC
3 dias
days
O
COOH
reflujoinen
EtOH
reflux
EtOH
62%
O
O
COOH
N
N
O
O
N
N
H
DIAD
N
O
N
N
NH2
75%
O
80%
COOH
WHAT ARE WE GOING TO DO TODAY?
Chemical reaction
Isolation of product by
filtration



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Characterisation of product by
chromatography
Let’s research!