how are medicines developed?

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:

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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 agentsDrug 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

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WHAT ARE WE GOING TO DO TODAY?

Let’s research!