CENTRO ESCOLAR UNIVERSITY - MALOLOS
COLLEGE OF PHARMACY – BSP3A-3
Drug Discovery and Development
Ma’am Penuel David
Module 1: Introduction to Drug Discovery and Development
INTRODUCTION: ▪ When the virus was first identified by two research groups in 1983,
there were few antiviral agents available, none provided effective
treatment for HIV infection and infection progressed rapidly to AIDS,
and finally death by opportunistic infection.
▪ By 1987, AZT (Retrovir®, Azidothymidine), the first reverse
transcriptase inhibitor, was approved for clinical application for the
treatment of HIV infection, and additional treatment options were
developed through the next three decades.
▪ The discovery of modern antiviral drugs such as Viread®
(Tenofovir), Zeffix® (Lamivudine) [reverse transcriptase
inhibitors], Viracept® (Nelfinavir), Norvir® (Ritonavir), and
Crixivan® (Indinavir) [HIV protease inhibitors] provided
additional treatment alternatives.
▪ In the late 1990s, multidrug cocktail treatment regimens, also
known as highly active antiretroviral therapy (HAART), were
introduced, further enhancing treatment options, culminating in
the development of all-in-one fixed combination medications such
as Complera® and Stribild®.
"While additional progress is still required, it is clear that modern drug
discovery and development changed the course of the AIDS epidemic in
less than three decades, allowing patients who were once given a death
sentence to lead productive lives."
This module provides an overview of the processes of drug
discovery and development. This serves as the foundation for the CANCER DRUG DEVELOPMENT:
following modules which describe the various functions involved in ▪ Cancer treatment has seen a similar transition, as survival rates for
drug discovery and development. many types of cancer have dramatically improved as a result of the
discovery and development of novel therapeutic agents.
Our aim is to help aspiring students whose research may be ▪ For instance, overall cancer death rates in the United States
relevant to drug discovery and/or development to frame their have declined by 27% between 1991 and 2016, and progress
research in a way that appropriately places their findings within the against some specific cancer types has been substantial.
drug discovery and development process and thereby support effective
translation of pre-clinical research to humans.
Cancer death
LEARNING OUTCOME OBJECTIVES: rates versus
At the end of this module, the student should be able to: counts for all
1. Discuss the scope of drug development including screening cancer types
through ethnographic research in relevant databases. combined,
2. Relate the basic biology of disease in generating hypothesis in the United
design, development and testing potential new therapies. States, 1990-
2016.
M1L1: OVERVIEW OF DRUG DISCOVERY AND DEVELOPMENT
▪ Over the course of the last 2 centuries, modern medicines have ▪ The identification of antitumor natural products and natural
improved the lives of countless patients. Diseases and conditions product analogs such as Taxol® (Paclitaxel), Velban®
that were once deemed incurable/fatal have been conquered (Vinblastine), Adriamycin (Doxorubicin), and Hycamtin®
with therapeutic agents designed to extend & improve quality of life. (Topotecan) has clearly demonstrated the importance of natural
products in modern medicine.
DISCOVERY OF ANTI-HIV DRUGS: "A significant portion of the improved clinical outcomes in cancer can
▪ The most recent, and perhaps most notable, of these be attributed to improved chemotherapeutic agents."
accomplishments is the transition seen in the consequences of
infection with human immunodeficiency virus (HIV), the virus
known to cause acquired immune deficiency syndrome (AIDS).
THE PROCESS:
▪ On the surface, providing a drug necessary to solve a medical
problem would seem to be a relatively simple task; one, identify
HIV on cell surfaces. the cause of the disease, and two, design a drug that will fix or
A gallery of Atomic Force eliminate the problem.
Microscopic images of HIV
particles emerging from or ▪ This is, of course, a very simplistic view, as there are many factors
attached to the surfaces of to consider beyond killing the offending organism. There are
human lymphocytes. millions of compounds that will kill an infectious organism, but you
have to consider these questions;
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CENTRO ESCOLAR UNIVERSITY - MALOLOS
COLLEGE OF PHARMACY – BSP3A-3
Drug Discovery and Development
Ma’am Penuel David
Module 1: Introduction to Drug Discovery and Development
1. Can these compounds do so without negatively impacting the host? A recent analysis of clinical trial success rates has indicated that only 1
2. Can these be delivered as safe & effective therapeutic agents? out of every 10 clinical candidates will successfully traverse clinical trials
3. How does one determine which are useful and which ones are not? and reach the market. This represents a success rate of less than
4. Of the useful compounds, which ones will be of interest to the 0.001% if measured by the number of compounds examined at the
companies that manufacture drugs and which ones will not? outset of the process.
▪ Given the large number of complex issues associated with drug
design & dev’t, it should be abundantly clear that no one individual The creation of a new drug can be broadly divided into two major stages:
could possibly conquer all of the tasks required to discover, 1. Drug Discovery = therapeutic concept → drug molecule.
develop, & successfully bring to market a new therapeutic 2. Drug Development = drug molecule → registered drug product.
entity. The process is a multidimensional one & as such requires the
coordinated effort of individuals with a wide array of expertise.
o In addition, it is important that any participant in this field DRUG DISCOVERY:
understands the magnitude of costs associated with pursuit of Drug Discovery
new drugs. The rewards for those who are successful can be ▪ Includes all of experimentation & studies designed from initial
substantial as indicated by the success of compounds. identification of a biological target & associated disease to
identification of single compound with potential to be clinically
relevant; may be further broken down into three distinct phases:
---BEST SELLING PHARMACEUTICALS OF 2018---
Rank Drug Main Trade 2018 1. Target Discovery
Indication Name Sales ▪ The choice of a disease area + identification of a biological
(Million target (enzyme, G-protein-coupled receptor, ion channel, etc.)
USD)
1 Adalimumab Rheumatoid Humira 19 936 2. Lead Discovery
Arthritis ▪ Structurally related compounds with the desired biological activity
3 Apixaban Anticoagulant Eliquis 9872 are identified (HIT and LEAD compounds) through biological
screening of large numbers of compounds.
4 Lenalidomide Multiple Revlimid 9685 3. Lead Optimization
Myeloma ▪ Lead compounds are modified (now become ANALOGS) and
5 Nivolumab Oncology Opdivo 7570 studied to identify potential candidate for drug development.
6 Pembrolizumab Oncology Keytruda 7171 DRUG DEVELOPMENT:
Drug Development
7 Etanercept Rheumatoid Enbrel 7126 ▪ Typically begins once a single compound has been identified,
Arthritis which is then progressed through various studies designed to
support its approval for sale by the appropriate regulatory bodies.
8 Trastuzumab Breast Cancer Herceptin 6981
1. Submission of an Investigational New Drug Application
9 Bevacizumab Colon Cancer Avastin 6847 ▪ INDA requests permission to move a clinical candidate into human
study. It provides regulatory agencies with detailed preclinical data
and detailed clinical protocols that describe how the compounds
10 Rituximab Non- Rituxan, 6750
will be studied in human populations.
Hodgkin's MabThera
Lymphoma
2. Clinical Trials (Phase I, II and III)
Phase I Safety and tolerability of an IND are examined in a
small number of healthy individuals, typically 20 to
▪ As of 2011, it is estimated that a single new drug costs over $1.75 100 people.
Billion to discover and develop. The costs and complexity of drug
discovery and development is staggering. Phase II Safety and efficacy of IND are determined in around
100 to 300 patients.
Phase III Efficacy of IND in larger population including
comparison with standard therapies.
3. Submission of New Drug Application (NDA) to regulatory body
▪ NDA typically contains comprehensive details of both animal and
human studies, all safety findings, manufacturing procedures,
detailed formulation information for all dosing methods studied,
and storage conditions.
4. Clinical Trial (Phase IV)/Post-Marketing Surveillance (PMS)
▪ PMS detects rare and long-term adverse effects across a much larger
population of patients than could be supported in Phase III.
Identification of a single marketed drug can require an initial ▪ Impact of PMS can include;
examination of over 100,000 candidate compounds, hundreds of o Alterations to labeling based on safety results,
preclinical animal studies, and numerous clinical trials involving o Contraindication for use of the new drug in combination
thousands of patients. with other medications, or withdrawal of marketing
approval if the findings are severe enough.
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CENTRO ESCOLAR UNIVERSITY - MALOLOS
COLLEGE OF PHARMACY – BSP3A-3
Drug Discovery and Development
Ma’am Penuel David
Module 1: Introduction to Drug Discovery and Development
▪ Companies often use the data in PMS to identify competitive ▪ Such ready-made, highly evolved biomolecules stand a better chance
advantages, new markets, and new indication for the products. of interacting with selected drug targets than do random synthetic
molecules and the pool from which they come is huge & largely
untapped.
M1L2: ETHNOPHARMACOLOGY & NATURAL PRODUCT RESEARCH ▪ In practice, the theoretical advantages of natural products are
balanced by several practical disadvantages such as;
▪ A glance at the pharmacopoeia will show that many therapeutic 1. Accessibility due to geographical, cultural, and political reasons
agents, particularly anti-infective and antineoplastic 2. Continuing availability of the active compound may be uncertain.
drugs, originate from natural products, rather than synthetic 3. Purification and structure determination of natural products is
molecules. often difficult and time-consuming.
"Exploiting such a ready-made compound library from natural
Examples of therapeutic drugs derived from natural products are products is seen as an attractive strategy for important therapeutic
shown in the following table. breakthroughs."
Warfarin ▪ Anticoagulant
▪ Synthetic compound derived from
dicoumarol, found in spoiled sweet clover
Heparin ▪ Anticoagulant
▪ Occurring naturally in mammalian tissues
Hirudin ▪ Anticoagulant
▪ From leech, now produced by genetic
engineering
Opiates ▪ Analgesic compounds from poppies
Methylxanthines ▪ Phosphodiesterase inhibitors + adenosine
(Caffeine, receptor antagonists
Theophylline) ▪ Produced by tea, coffee, and coca plants
Statins ▪ HMG CoA reductase inhibitors used to
reduce plasma cholesterol
▪ Lovastatin is a fungal metabolite. Later
compounds (mevastatin, pravastatin)
synthesized from lovastatin.
Cromoglycate ▪ Asthma prophylaxis
▪ Synthetic compound based on khellin; a
plant product used as an herbal medicine
Vinca Alkaloids ▪ Anticancer drugs produced by plants of
(Vincristine, the periwinkle family
Vinblastine)
Paclitaxel ▪ Anticancer drug from yew tree
Etoposide ▪ Anticancer drug
▪ Synthesized from podophyllotoxin,
produced by mandrake plant
▪ Used in folk medicine
Artemether ▪ Antimalarial drug
▪ Semi-synthetic derivative of artemesin,
produced by Chinese herb
Ivermectin ▪ Antihelminthic drug
▪ Semi-synthetic derivative of avermectin,
a fungal metabolite
Antibiotics ▪ Too numerous to list. The majority of
current antibiotics are derived from
fungal metabolites.
▪ Until about 1950, when synthetic chemistry really came into its
own as a source of new drugs, most of the pharmacopoeia consisted
of natural products, and they continue to be important.
