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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)
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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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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Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Alexander Fleming
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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ClH.H2N HO As As
NH2.HCl OH
Salvarsan
Alexander Fleming
Louis Pasteur
Robert Koch
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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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
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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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Assay Development
Approximately 1% of the compounds from HTS: to demonstrate some level of antagonistic or agonistic effectspotential hits Primary & secondary screening
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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- 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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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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
Clinical studies
Phase-I/II/III/IV
Market
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Drug discovery-development process :- more expensive, important to look at new ways to bring forward NCEs New Chemical Entities:
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Continued
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Taxus brevifolia
Vincristine
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Papaver bracteatum
Papaver somniferum
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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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
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Superposition of nicotine (cyan) and epibatidine (red). Nitrogens are blue; chlorine is green.
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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D. polylepis
Angiotensin-converting enzyme inhibitor (ACE inhibitor) Hypertension and some types of congestive heart failure
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Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
Medicines From Marine Sources:- Algae Brevitoxin (nurotoxin)- suit of cyclic polyether compounds produced naturally by species of marine (algal bloom) dinoflagellate Karenia brevis
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Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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We know a very little about the Nature, there is lot more to discover from it!!!
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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Thank you
Training programme for AYUSH, Lecture, 1st Apr 10, S D Sawant, Medicinal Chemistry Division
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