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Drug discovery and
development
Drug discovery and development
The discovery phase
The development phase
Pre-discovery
Gather as much information as possible about
the disease and try to understand its nature.
Pre-clinical testing
In vitro and in vivo testing to determine if the drug is safe
enough for human testing.
Target identification
Choose a molecule in the body to target with a
drug; often a protein.
Clinical trial exceptions (CTX) applications
File CTX with appropriate authorities before clinical testing can
begin.
Target validation
Test the target and confirm its role in the
disease.
Phase 1 clinical trial
Initial human testing in a small group of healthy volunteers.
Drug discovery
Find a promising molecule (a ‘lead compound’)
that could become a drug.
Phase 2 clinical trial
Test in a small group of patients.
Phase 3 clinical trial
Test in a large group of patients to show safety and efficacy.
Early safety tests
Initial tests on lead compounds, including
pharmacokinetics, by experiment and/or
computer modelling.
Marketing authorisation application
Apply to appropriate authorities for approval.
Lead optimisation
Alter the structure of lead candidates to
improve properties; this may include
formulation, delivery mechanism and scale-up.
On-going studies and Phase 4 trials
Continuing monitoring and checking of the drug in use.
Manufacturing
Begin full-scale production.
Drug discovery and development
Drug targets
Drug design
A target is a molecule that the drug needs to find and
act upon. Often it is a protein molecule such as an
enzyme.
Modern technologies allow chemists to work out the
molecular structure of a target molecule and
represent it using physical or computer-generated
models. This enables them to investigate the
interaction of potential drug molecules with the target.
Increasingly, the starting point for the design of new
drug is an understanding at the molecular level of the
disease to be treated.
Drug discovery and development
Looking for a lead compound
Lead optimisation and scale up
With the target identified, thousands of compounds
are made using a technique called combinatorial
chemistry. These are narrowed down to one
compound to be studied further. This is the lead
compound.
The lead compound chemically modified to produce a
number of structurally similar compounds. The is
done by parallel synthesis. From these the most
likely one is chosen for pre-clinical testing. This is
followed by scaling up, through pilot scale to
manufacture.
Drug discovery and development
Clinical trials
A case study in drug discovery and development
Any new medicinal drug must undergo a series of
rigorous clinical trials to show its effectiveness and
safety.
In 2011, the Ekjut
Trial in
Jharkhand and
Orissa was
awarded Trial of
the Year by the
Society for
Clinical Trials.
The NHS has produced a video in which Dr Ben
Goldacre explains why clinical trials are important,
what they involve and who can take part in one. He
also describes common concerns patients might have
and gives tips on what questions to ask before taking
part in any research.
http://www.nhs.uk/Conditions/Clinicaltrials/Pages/Introduction.aspx?url=Pages%2FWhatis-it.aspx
… the discovery of zanamivir
Zanamivir is a treatment for
influenza caused by influenza
A virus and influenza B virus.
It was discovered in 1989 and
is marketed by GSK under the
trade name Relenza.
Physiochemical properties
Pharmacokinetics
It falls into a number of areas:
•
Liberation: release of a drug from its
administered form
•
Absorption: movement of a drug from where
it is liberated into the bloodstream
Distribution: process by which a drug passes
from the bloodstream to body tissues and
organs
•
Metabolism: chemical reactions that change
drugs into compounds which are easier to
eliminate
•
Excretion: elimination of unchanged drug or
metabolite from the body
•
Toxicity: harmful side-effects a drug may
have
These have the acronym LADMET
High throughput
screening of
ADME
Early stages of
drug discovery
Later stages of
drug discovery
LADMET screening,
e.g. cell cultures
Pharmacokinetic profile
and toxicity studies
using living organisms
Lead
optimisation
Preclinical
trials
Measurement by experiment
•
ADME prediction
by molecular
modelling
Prediction from modelling
Pharmacokinetics is the study of what the body
does to a drug. Understanding this is key in drug
discovery and development.
From discovery to clinical trials
Pharmacokinetic properties of drugs are studied
throughout the discovery and development process.
Physiochemical properties
LADMET and drug discovery and development
Measurement of the physiochemical properties of drugs has always been important, but high throughput and
fast ADME profiling has become increasingly important as scientists seek ways of shortening the drug discovery
and development process.
The following extract is taken from an article by Dr Jianling Wang and Dr Laszlo Urban in Drug Discovery World
(2004).
The increased costs in the discovery and development of new drugs, due in part to the high attrition rate of drug
candidates in development, has led to a new strategy to introduce early, parallel evaluation of efficacy and
biopharmaceutical properties of drug candidates.
Investigation of terminated projects revealed that the primary cause for drug failure in the development phase
was the poor pharmacokinetic and ADMET (Absorption, Distribution, Metabolism, Discretion and Toxicity)
properties rather than unsatisfactory efficacy. In addition, the applications of parallel synthesis and combinatory
chemistry to expedite lead finding and lead optimisation processes has shifted the chemical libraries towards
poorer biopharmaceutical properties.
Establishments of high throughput and fast ADMET profiling assays allow for the prioritisation of leads or drug
candidates by their biopharmaceutical properties in parallel with optimisation of their efficacy at early discovery
phases. This is expected to not only improve the overall quality of drug candidates and therefore the probability
of their success, but also shorten the drug discovery and development process.
Physiochemical properties
Physical chemistry and LADMET
Instrumentation
The biological and chemical changes that happen
when a drug is taken are extremely complicated.
Yet an understanding them is key to the
identification of a lead compound and its
optimisation.
The understanding of drug liberation, absorption,
distribution, metabolism, excretion and toxicity
(LADMET) is underpinned by physical chemistry
concepts and principles that include:
•
the physical properties of materials;
•
solubility and rates of dissolution;
•
pH and dissociation of weak and strong acids;
•
thermodynamics and rates of diffusion;
•
partition and distribution coefficients;
•
molecular shapes, charge distribution and
polar surface area;
•
intermolecular bonding.
The instrument shown above can measure solubility, rate of
dissolution, dissociation constants and distribution/partition
coefficients – and on a very small scale.
Instruments are also available to study the permeation of
molecules using artificial membranes.
•
PAMPA uses an artificial lipid membrane.
•
Caco-2 uses an artificial membrane made from human cells.