Stages Drug Discovery

8/2/2019 Stages Drug Discovery

1/33

Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division 7

Sanghapal D Sawant

Medicinal Chemistry Division, IIIM-Jammu

Stages of Drug DiscoveryStages of Drug Discovery


2/33

71

Natural Products as the guiding principleof drug discovery/(NCEs)

Moving Beyond Natural Products

Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division


3/33

72

- What is drug discovery and development, and what are the differences ?Drug Discovery:-

Notions such as ``reality'' and ``observation'' are used to explain Serendipity (may unravel in shortest time period)

Majorly failures in Drug Discovery- when passes to development

Drug Development:-

Next step to discovery- Fine-tuning & interdisciplinary approach Highly engineered/designed program and some times based on

hypothesis

Time consuming and expensive

High uncertainty in success rate

Introduction:-

Several firms work on, to find out a NCE (Drug Discovery),

Development can be outsourced to external agencies -Expensive task



4/33

73

Medicine: Approaches/Therapies used for medicine

Traditional medicines: Folk medicines/indigenous medicines

(Chinese medicine, Indian folk medicine, Ancient Iranian,

Islamic, Acupuncture, herbal, Muti, Ifa, etc)

Ayurveda Unani

Sidhha

Homeopathy

Allopathy: Drugs from natural sources/synthetic drugs



5/33

74

A Magic Mystery-Discovery:-Acetyl Salicylic Acid (Aspirin) Rev Edward Stone, 1760s found Willow bark-effective in reducing fever, was

being used for several centuries by Americans

Willow bark contains salicin, isolated-crystalline form-1828

Metabolized in vivo to the active agent Salicylic acid

Bayer AG introduced aspirin to the world more than a century ago in 1899. In

1915, Aspirin - the first drug to be processed in tablet form - became available

without a prescription. It remains the Gold standard among painkillers to this

day, and recent findings have even shown the drug to prevent heart attacks and

strokes.

In 1897, Dr. Felix Hoffman, synthesized ASA, but the young Bayer

researcher didnt realize the significance of his achievement, in

creating ASA, he developed the active ingredient for the best-

known and most frequently used medicine in the world: Aspirin

History of Drug Discovery:-

ASA (Asipirin): Used exhaustively in Spanish flu pandemic, 1918

Mechanism of action is still not completely known-MysteryTraining programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division


6/33

75

History of Drug Discovery:-



7/33


8/33

77

Pioneers in Development of Medicinal Chemistry

H2N

AsHO O

O

Atoxyl

AsAsHO OH

ClH.H2N NH2.HCl

Salvarsan

Na+

Alexander Fleming

Louis PasteurRobert Koch



9/33

78

Early 19th century - extraction of compounds from plants (morphine,

cocaine, etc)-used for medicinal use

Late 19th century - less natural products used, more synthetic substances

utilized. Dye and other chemical companies started research labsand discovered medical applications

Early 20th century, 1905- John Langley-theory of receptive substances

Mid to late 20th century - understanding disease states, biological

structures (targets), processes, drug transport, distribution, metabolism, etc. Industry devoted solely to pharmaceuticals begins

Medicinal chemists used this knowledge to modify chemical structure to

influence a drugs activity, stability, etc.- Drug development started

Example: procaine = local anesthetic; Procainamide = anti-arrhythmic

Recent Developments in

Medicinal chemistry / Drug Discovery :-

H2N

O

NHCH2CH2N(C2H5)2H2N

O

OCH2CH2N(C2H5)2

Procaine Procainamide

Alfred Einhorn



10/33

79

Todays Pharmaceutical Business

Interdisciplinary!!!



11/33

10

Target Identification

Target validationAssay development

High throughput screening

Lead selectionLead optimization

Candidate selection

DMPK/ADMETClinical trials

Market

A Typical Drug discovery & development program:-

Timeli

nes10-12

years

,

sometim

esupto2

0year

s

500 million to 2,000 million dollars

Drug Discovery & Development



12/33

711

1. Target IdentificationTypes of targets

Therapeutic target classes

Target Discovery



13/33

712

2. Target Validation Validation techniques range from in vitro

approaches to whole animal models to verification

of target manipulation in diseased humans

Wortamanin-nonspecific

Liphagal PI3K-alpha inhibitor



14/33

713

InformaticsMolecular Concept or software uses locks (biological targets) and keys

(drugs) to illustrate the concepts involved in drug discovery

One candidate in thousands or millions-less success rate,

only successful candidate-Imatinib

A molecule can be designed

that has optimal (more)

interactions with the target

protein than the originalinhibitor



15/33

714

Hit to Lead Selection

Approximately 1% of the compounds from HTS: to

demonstrate some level of antagonistic or agonistic effects-

potential hits

Primary & secondary screening

Hit confirmation:- clusters of several compound will

be chosen according to their characteristics

Assay Development

The HTS -first step in the process of filtering out potential

hits to be optimized as downstream drug candidates

High Throughput Screening



16/33


17/33

816

Candidate selection

Ronald Sarver, Pfizer, Inc.

Selecting the leads from secondary

screening

Proven specificity and the highestbinding affinities to the target of interest

Often binding affinities start off in the

110 M range, requiring potencyimprovements of up to five orders on

magnitude before they would be

considered viable drug candidates

Toxicity and bioavailability

Structural information from ligand-

target X-ray crystallization

Candidate selectionTraining programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division


18/33

717

Pre-clinical and Clinical studies

Clinicalstudies Phase-I/II/III/IVMarket



19/33

718

Financial inputs- Cost for launching a new drug in market:-

2003 report an average pre-tax cost of approximately $800 million to bring a new

drug (i.e. a drug with a New Chemical Entity) to market

2006 estimates states that costs vary from around 500 million to 2,000 million

dollars depending on the therapy or the developing firm

These figures relate only to new, innovative drugs (drugs with a New Chemical

Entity NCE, also called New Active Substance NAS)

Each year, worldwide, only about 26 such drugs enter the market (2005: 26, 2004:

24, 2003: 26, 2002: 28)

About 29% of total cost is spent on FDA-required clinical trials

Drug discovery process :- more expensive, important to look at new ways to bring

forward NCEsTraining programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division


20/33

719

R&D expenditure Vs NDA-FDA



21/33

720

US-FDA Drugs approved in 2008



22/33

721

Natural Sources of DrugsBacteria

Plants: Terrestrial or Marine, Algae, Lichens and Fungi

Higher Plants

Animals: Terrestrial and marine;Amphibians, insects, reptiles

New Chemical Entities:

Drug discovery-development process :- more expensive,

important to look at new ways to bring forward NCEs



23/33

722

New Chemical Entities:

A new chemical entity (NCE) (also known as new molecular entity (NME)) is a drug that

contains no active moiety that has been approved by FDA in any other application

submitted under section 505(b) of the Federal Food Drug and Cosmetic Act

A NCE is a chemical molecule developed by the innovator company in the early drug

discovery stage, which after undergoing clinical trials could translate into a drug that could

be a cure for some disease.

Synthesis of NCE is the first step in the process of development of drug

In the latter option, companies can avoid the expensive and lengthy process of clinical trials,

as the licensee company would be conducting further clinical trials and subsequently

launching the drug

Companies adopting this model, huge margin by one time payment apart from revenue

sharing agreement with the licensee company



24/33

723

Plant kingdom-Artemisinin fromArtemisia annua-Antimalerial

morphine, cocaine, digitalis, quinine, tubocurarine, nicotine, and muscarine

Animal kingdom- Exenatide from lizard Diabetes type-2 The marine world:-Coral, sponges, fish & and marine microorganisms

Curacin-A from Cyanobacterium sp.-Antitumor

Venoms and toxins:- Animals, plants, snakes, spiders, scorpions, insects and

microorganisms- Tetrodotoxinfrompuffer fish- Ion channel

Microbial sources- Antibacterial agents such as the cephalosporins, tetracyclins,

aminoglycosides, rifamycins and chloramphenicol

Asperlicin- isolated fromAspergillus alliaceusBorrelidin from Streptomyces parvulus

Amphotericin-B from Streptomyces nodosus-Anti-fungal

New Chemical Entities: Natural sources

Continued



25/33

724

Taxus brevifolia

Vincristine

Medicines From Plants



26/33

725

Medicines From Plants

Papaver somniferum

Papaver bracteatum



27/33

726

Medicines From Animals

STORY OFEPIBATIDINE

What's in a frog?

The frogs were so toxic, arrow tips only had to be rubbed across the back of a frogto coat them with poison

paralysis even in the minute doses

2 miligram can kill a person

discovered that the toxin also held potent analgesic (painkilling) effects surpassing

even opioids such as morphine



28/33

727

Dr. John Daly

Superposition of nicotine (cyan) andepibatidine (red).

Nitrogens are blue; chlorine is green.

What's in a frog?

Medicines From Animals

similar structure to nicotine



29/33


30/33

729

K C Nicolaou& coworkers

in 1995 Synthesized in

123 steps

Brevitoxin (nurotoxin)- suit of cyclic

polyether compounds produced naturally by

species of marine (algal bloom) dinoflagellate

Karenia brevis

Medicines From Marine Sources:- Algae



31/33

730

Natural Molecules Need not

be the best Drugs



32/33

731

We know a very little about the Nature,We know a very little about the Nature,

there is lot more to discover from itthere is lot more to discover from it!!!!!!



33/33

732

Thank youThank you


Documents

Stages Drug Discovery