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Transcript
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: ? 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 28 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 ? Characterisation of product by chromatography Let’s research!