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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
Therapeutic target
Active ingredient
It looks for the therapeutic target to have an effect and cure the disease
How are medicines developed?
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)
CLINICAL DEVELOPMENT
PHASE I PHASE II PHASE III
Launch of thedrug
PHASE IV
Launch of thedrug
PHASE IV
DEVELOPMENT SEQUENCE IN THE SEARCH FOR A MEDICINE
PRECLINICALSTUDIES
(2-6 years)
In vitro/In vivo
• A drug candidate can be discovered in different ways:
?
HOW IS A DRUG CANDIDATE DISCOVERED?
A drug candidate can be discovered in different ways:
Chemical modification
Serendipity chance
Massive screening
Rational design
HOW IS A DRUG CANDIDATE DISCOVERED?
WE NOW HAVE A DRUG CANDIDATE!
• A thorough and complete preclinical study is required before we can test a drug in humans:
• These preclinical studies include:
– Stability and toxicity studies
– In-vitro tests (proteins, cells, tissues and organs)
– In-vivo tests (animals)
PRECLINICAL DEVELOPMENT
©Parc Científic Barcelona. Author: J. Planagumà
• Clinical development is the longest and most costly part of the search for new medicines. It consists of three phases:
PHASE IPHASE II PHASE III
Healthy volunteers
Safety and dose
Patients (100-300)
(drug or placebo)
Efficacy and side
effects
Patients(1300-3000)
Long-termeffects
CLINICAL DEVELOPMENT
• If the drug has successfully passed the three clinical phases, it is launched on the market, but the study continues (Phase IV)
PHASE IIPHASE III
PHASE IVPHASE I
MARKET
AND FINALLY… THE DRUG IS LAUNCHED ON THE MARKET!
SEARCH for DRUGS for
PARKINSON’S DISEASE
The Barcelona Science Park research project
• 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 – WHAT IS PARKINSON’S DISEASE?
• Our brain is our body’s control centre and the cells responsible for it are called neurons. These cells self-regenerate 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 is responsible for transmitting the signals required to control the movement of our muscles.
• A dopamine deficiency therefore leads to an imbalance in neuronal transmission, preventing neurons from communicating properly. This leads to a loss of motor function.
• Dopamine Control of movement
Low dopamine levels Difficulties in the control
of movement
• Dopamine Control of movement
Low dopamine levels Difficulties in the control
of movement
INTRODUCTION – PARKINSON’S DISEASE, CAUSES
• The way to treat the disease’s progression is by taking oral medicines.
• The most commonly used medicine today is levodopa, or L-dopa, which consists of a chemical compound that the brain uses to produce dopamine.
INTRODUCTION – PARKINSON’S DISEASE, TREATMENT
tyrosine
L-dopa
dopaminevesicles with the dopamine transmitter
dopamine receptor
receptor cell
synapse
• Other medicines, which imitate the effect of dopamine in the brain, are also used. – e.g. bromocriptine, lisuride, pergolide, ropinirole, etc.
receptorreceptor
imitator
Cell membrane
Cell membrane
dopamine
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.
INTRODUCTION – PARKINSON’S DISEASE, TREATMENT
• 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 D
• 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.
Anti-Parkinson’s agents
Drug cocktail A single drug
RESEARCH, SYNTHESIS OF DRUGS FOR THE TREATMENT OF PARKINSON’S DISEASE
Cell response
New drug
RESEARCH, SYNTHESIS OF DRUGS FOR THE TREATMENT OF PARKINSON’S DISEASE
N
N NH
N
O
O
OOH
O A D
(±)-PPHT
A D
OH
N
NH2
XAC-COOH
RESEARCH, DESIGN AND SYNTHESIS OF NEW MOLECULES
HN
HN
O
CNHOOC
Ac2ON
OCN
NH
O
N
N
O
O
NH2
N
N
O
O
NH2
NO
NaNO2
Na2S2O4N
N
O
O
NH2
NH2
N
N
O
O
NH2
N
OCOOH
N
N NH
N
O
O
O
COOH
OHC O COOH
DIAD
OHC OH COOHI K2CO3
+
2 h, 80 ºC
pH 10-11
NaOH 70%
EtOAc/H2O
reflujo en EtOHDMF, 60ºC3 dias
96% 96%
75%
76%
80%75%
62%
AcOH
+
HOW DO WE SYNTHESISE THESE NEW MOLECULES IN THE LAB?
27
HN
HN
O
CNHOOC
Ac2ON
OCN
NH
O
N
N
O
O
NH2
N
N
O
O
NH2
NO
NaNO2
Na2S2O4N
N
O
O
NH2
NH2
N
N
O
O
NH2
N
OCOOH
N
N NH
N
O
O
O
COOH
OHC O COOH
DIAD
OHC OH COOHI K2CO3
+
2 h, 80 ºC
pH 10-11
NaOH 70%
EtOAc/H2O
reflujo en EtOHDMF, 60ºC3 dias
96% 96%
75%
76%
80%75%
62%
AcOH
+
HOW DO WE SYNTHESISE THESE NEW MOLECULES IN THE LAB?
days
reflux in EtOH
28
HN
HN
O
CNHOOC
Ac2ON
OCN
NH
O
N
N
O
O
NH2
N
N
O
O
NH2
NO
NaNO2
Na2S2O4N
N
O
O
NH2
NH2
N
N
O
O
NH2
N
OCOOH
N
N NH
N
O
O
O
COOH
OHC O COOH
DIAD
OHC OH COOHI K2CO3
+
2 h, 80 ºC
pH 10-11
NaOH 70%
EtOAc/H2O
reflujo en EtOHDMF, 60ºC3 dias
96% 96%
75%
76%
80%75%
62%
AcOH
+
1. Chemical reaction
HOW DO WE SYNTHESISE THESE NEW MOLECULES IN THE LAB?
2. Isolation and purification of the product
3. Characterisation of the product
HOW DO WE SYNTHESISE THESE NEW MOLECULES IN THE LAB?
WHAT ARE WE
GOING TO DO
TODAY?
HN
HN
O
CNHOOC
Ac2ON
OCN
NH
O
N
N
O
O
NH2
N
N
O
O
NH2
NO
NaNO2
Na2S2O4N
N
O
O
NH2
NH2
N
N
O
O
NH2
N
OCOOH
N
N NH
N
O
O
O
COOH
OHC O COOH
DIAD
OHC OH COOHI K2CO3
+
2 h, 80 ºC
pH 10-11
NaOH 70%
EtOAc/H2O
reflujo en EtOHDMF, 60ºC3 dias
96% 96%
75%
76%
80%75%
62%
AcOH
+
Chemical reaction
HOW DO WE SYNTHESISE THESE NEW MOLECULES IN THE LAB?
days
reflux in EtOH
Chemical reaction
Isolation of product by filtration
Characterisation of product by chromatography
?
WHAT ARE WE GOING TO DO TODAY?
Let’s research!
