Stages Drug Discovery

Stages of Drug Discovery
Sanghapal D Sawant Medicinal Chemistry Division, IIIM-Jammu
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
Moving Beyond Natural Products Natural Products as the guiding principle of drug discovery/(NCEs)
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Introduction:- 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
Several firms work on, to find out a NCE (Drug Discovery), Development can be outsourced to external agencies -Expensive task
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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
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History of Drug Discovery: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 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 bestknown and most frequently used medicine in the world: Aspirin
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.
ASA (Asipirin): Used exhaustively in Spanish flu pandemic, 1918 Mechanism of action is still not completely known-Mystery
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History of Drug Discovery:-
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History of Drug Discovery:-
Sulfanilamide, 1932 First antibiotic Prontosilby Bayer AG
Alexander Fleming
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Pioneers in Development of Medicinal Chemistry
HO O As O H2N Atoxyl Na+
ClH.H2N HO As As
NH2.HCl OH
Salvarsan
Alexander Fleming
Louis Pasteur
Robert Koch
Recent Developments in Medicinal chemistry / Drug Discovery : 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 labs and 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
O H 2N OCH2CH2N(C2H5 )2 Procaine H 2N O NHCH2CH 2N(C 2H5) 2 Procainamide
Alfred Einhorn
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Todays Pharmaceutical Business Interdisciplinary!!!
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Drug Discovery & Development

A Typical Drug discovery & development program:-
rs, rs a Market ye yea -12 20 0 Clinical trials s 1 p to e lin es u DMPK/ADMET e im Tim e t Candidate selection om s Lead optimization
Lead selection High throughput screening Assay development Target validation Target Identification 500 million to 2,000 million dollars
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Target Discovery 1. Target Identification Types of targets
Therapeutic target classes
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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

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Informatics Molecular Concept or software uses locks (biological targets) and keys (drugs) to illustrate the concepts involved in drug discovery
A molecule can be designed that has optimal (more) interactions with the target protein than the original inhibitor
One candidate in thousands or millions-less success rate, only successful candidate-Imatinib
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Hit to Lead Selection

Hit confirmation:- clusters of several compound will be chosen according to their characteristics
High Throughput Screening

The HTS -first step in the process of filtering out potential hits to be optimized as downstream drug candidates
Assay Development
Approximately 1% of the compounds from HTS: to demonstrate some level of antagonistic or agonistic effectspotential hits Primary & secondary screening
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Lead Discovery and optimization

Several parameters Primary and secondary screening
- have compound members that exhibit a high affinity towards the target (less than 1 M) - show chemical tractability (suitability of a compound for chemical modification) - be free of Intellectual property - not interfere with the P450 enzymes nor with the PGPs - not bind to human serum albumin - be soluble in water(above 100 M) - be stable - have a good drug-likeness - exhibit cell membrane permeability - show significant biological activity in a cellular assay - not exhibit cytotoxicity - not be metabolized rapidly
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Candidate selection
Selecting the leads from secondary screening Proven specificity and the highest binding affinities to the target of interest Often binding affinities start off in the 110 M range, requiring potency improvements of up to five orders on magnitude before they would be considered viable drug candidates Toxicity and bioavailability Structural information from ligandtarget X-ray crystallization Ronald Sarver, Pfizer, Inc. Candidate selection 16 8 Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
Pre-clinical and Clinical studies
Clinical studies
Phase-I/II/III/IV
Market
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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 NCEs 18 7 Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
R&D expenditure Vs NDA-FDA
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US-FDA Drugs approved in 2008
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Drug discovery-development process :- more expensive, important to look at new ways to bring forward NCEs New Chemical Entities:
Natural Sources of Drugs

Bacteria Plants: Terrestrial or Marine, Algae, Lichens and Fungi Higher Plants Animals: Terrestrial and marine; Amphibians, insects, reptiles
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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
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New Chemical Entities: Natural sources

Plant kingdom-Artemisinin from Artemisia 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- Tetrodotoxin from puffer fish- Ion channel Microbial sources- Antibacterial agents such as the cephalosporins, tetracyclins, aminoglycosides, rifamycins and chloramphenicol Asperlicin- isolated from Aspergillus alliaceus Borrelidin from Streptomyces parvulus Amphotericin-B from Streptomyces nodosus-Anti-fungal
Continued
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Medicines From Plants
Taxus brevifolia
Vincristine
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Medicines From Plants
Papaver bracteatum
Papaver somniferum
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Medicines From Animals
What's in a frog?
STORY OF EPIBATIDINE back of a frog The frogs were so toxic, arrow tips only had to be rubbed across the
to 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
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Medicines From Animals

What's in a frog?
Dr. John Daly
Superposition of nicotine (cyan) and epibatidine (red). Nitrogens are blue; chlorine is green.
similar structure to nicotine
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Medicines From Animals The Mamba Strikes
Drugs from Serpents
D. polylepis
Bristol-Myers Squibb, Capoten
Dendroaspis viridis Green mumba, Africa
Angiotensin-converting enzyme inhibitor (ACE inhibitor) Hypertension and some types of congestive heart failure
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Medicines From Marine Sources:- Algae Brevitoxin (nurotoxin)- suit of cyclic polyether compounds produced naturally by species of marine (algal bloom) dinoflagellate Karenia brevis
K C Nicolaou & coworkers in 1995 Synthesized in 123 steps

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Natural Molecules Need not be the best Drugs
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We know a very little about the Nature, there is lot more to discover from it!!!
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Thank you
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Stages Drug Discovery

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Stages Drug Discovery

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Stages of Drug Discovery

Sanghapal D Sawant Medicinal Chemistry Division, IIIM-Jammu

History of Drug Discovery:A Magic Mystery-Discovery:-Acetyl Salicylic Acid (Aspirin)

History of Drug Discovery:-

History of Drug Discovery:-

Sulfanilamide, 1932 First antibiotic Prontosilby Bayer AG

Pioneers in Development of Medicinal Chemistry

HO O As O H2N Atoxyl Na+

Todays Pharmaceutical Business Interdisciplinary!!!

Drug Discovery & Development

Target Discovery 1. Target Identification Types of targets

Therapeutic target classes

Wortamanin-nonspecific Liphagal PI3K-alpha inhibitor

Hit to Lead Selection

High Throughput Screening

Lead Discovery and optimization

Pre-clinical and Clinical studies

R&D expenditure Vs NDA-FDA

US-FDA Drugs approved in 2008

Natural Sources of Drugs

New Chemical Entities:

New Chemical Entities: Natural sources

Medicines From Plants

Medicines From Plants

Medicines From Animals

Medicines From Animals

Dr. John Daly

similar structure to nicotine

Medicines From Animals The Mamba Strikes

Drugs from Serpents

Bristol-Myers Squibb, Capoten

Dendroaspis viridis Green mumba, Africa

K C Nicolaou & coworkers in 1995 Synthesized in 123 steps

Natural Molecules Need not be the best Drugs

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