Đây là bài giảng cho các lớp cao học ngành kỹ thuật hoá học về các khám phá và phát triển trong lĩnh vực hoá dược, tài liệu được trình bày bằng tiếng anh, rất hữu ích cho các bạn vì có nhiều hình ảnh minh hoạ các khám phá trong lịch sử hoá dược.
REFERENCES G. L. Patrick, An introduction to medicinal chemistry, Oxford university press 2005 Anthony J. Hickey, David Ganderton, Pharmaceutical Process Engineering, Informa Healthcare USA, Inc 2010. Bianca Piachaud, Outsourcing R&D in the Pharmaceutical Industry , Bianca Piachaud 2004. Bill Bennett, Graham Cole, Pharmaceutical production – An engineering guide, Chemical Engineers (IChemE) 2003. Michael Levin, Pharmaceutical Process Scale-up, Marcel Dekker, Inc 2002. David G. Watson, Pharmaceutical Analysis, Harcourt Publishers 1999. Gary Walsh, Brendan Murphy, Biopharmaceuticals - An industrial perspective, Kluwer Academic Publishers 1999. (C) HKD 2013 HISTORY IN BRIEF Primitive traces of medicinal chemistry: 9 Clay tablets (2600 BC, Sumérie): 1000 plants. 9 Ebers Papyrus (1500 BC, Egypt): 800 preparations. 9 Hippocrates (440-377 BC). … until 19th century: preponderance of plant-based potion. 9 Empiricism and theory of signature: similarity in characteristics of plants and the organ. Ex: Color Red / Bood () haemostatic derived from hibiscus). Shape / Organ (crocus bulb for gout treatment, big toe). (C) HKD 2013 HISTORY IN BIEF 1763: medicinal properties of extract of willow bark and leaves observed Edward Stone (headache, stomachache, and other body pain). 1829: Isolation of salicin by H. Leroux 1853: Transformation from salicin to acetyl salicylic acid by Charles Gerhardt. 1899: Bayer’s market launch of Aspirine. (C) HKD 2013 HISTORY IN BRIEF From 19 th century: DRUG = PURE COMPOUND. 9 1803: Isolation of morphine from opium poppy by Friedrich Serturner. 9 1819-1820: Isolation of strychnine, caffeine, quinine and colchicine by Pelletier and Caventou End of 19 th century – Beginning of 20 th century: 9 “Lock - Key” (E. Fisher). 9 “Magic Bullet” (P. Ehrlich): structure – activity. (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT DISCOVERY PHASE Choice of malady (medical demands, economic factors , strategy of lab, concurence). Choice of therapeutic target (mechanism, pertinence, distribution, selectivity, cells). Choice of biological test (in vitro, in vivo, method of screening, number of compounds). Screening and selection of lead (isolation, structure, patent). Elimination of molecules being difficult to project (complex structure, stability, toxicity). Lead substances (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT OPTIMIZATION PHASE Studying of Structure – Activity Relationships (SAR). Identificaiton of pharmacophore Optimization of pharmacodynamic properties. Optimization of pharmacokinetic properties and solubility. The best molecule (less toxic, in-vivo active, formulable) (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT OPTIMIZATION PHASE M. McCoss, Organic chemistry in drug discovery, T. A. Baillie Science 2004, 303, 1810 (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT PRECLINICAL PHASE (animal test) Exact knowledge of the molecule (pilot scale synthesis with purity > 99% , clearly identified impurities, stability within 6 month, available galenic form). Toxicity (acute, chronic, sub-chronic (5- 90 days)). Evaluation of mutagenic risk. Studying of effects on reproduction (fertility, embryo, death and postnatality) . Assurance of security in the test on human (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT CLINICAL PHASE I The first administration to human (~ 1 year with > 100-200 volunteers → 5- 30 kg). Studying clinical and biological tolerance on human. Determination of maximum tolerated dose (1 st administrated dose = 1/ 10 maximum dose without unacceptable toxicity on animal). Verification of pharmacokinetic properties . CLINICAL PHASE IIa: verification of therapeutic effects and side effects in short term. End of development research: molecule = medication ? Beginning of industrial development: molecule medication. (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT CLINICAL PHASE IIb Determination of effective therapeutic dose, dosage and type of administration (~ 2 years on 20-80 volunteers → 30-100 kg). Double blind test / placebo or existing medications (cancer or AIDS). (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT CLINICAL PHASE III (~ 3 years, 50-300 kg) Demonstration of surety and effectiveness of novel medication (larger population of patients). Comparison with drugs already on the market. (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT INTERNATIONAL REGISTRATION Favorable ratio of Benefits – Risks. Impeccable pharmaceutical quality. Safety methods in preclinical and clinical trials. Clinical effectiveness proved in claimed indication. PHARMACOVIGILANCE (CLINICAL PHASE IV) (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT (C) HKD 2013 DRUG DISCOVERY AND DEVELOPMENT 20 years patented. Supplementary protection certificate (SPC). (C) HKD 2013 DRUG DEFINITION Drug: at molecular scale, drug means a substance being able to interact with a biological system in order to give a biological response. Official definition of Drug: a drug is a chemical substance which may have medicinal, intoxicating, performance enhancing or other effects when taken or put into a human body or the body of another animal and is used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well- being . Drug = active ingredient + excipient. Excipient: 9 Carrier for active ingredients. 9 Stabilize the active ingredient. 9 Antiadherents (magnesium stearate), Binders(saccharide, protein, polymer). 9 Disintegrants. 9 Fillers (lactose, sucrose, glucose, mannitol, sorbitol). 9 Flavours, Colors , Preservatives , Sweeteners. (C) HKD 2013 DRUG DISCOVERY Source of Drugs → 52% drugs from nature or nature-inspired. Atorvastatine (Lipitor): best-seller drugs – 11 billions USD in 2004. (C) HKD 2013 DRUG DISCOVERY Natural molecules M. S. Butler, Nat. Prod. Rep. 2005, 22, 1620. Frogs Fishes Snakes (C) HKD 2013 DRUG DISCOVERY Natural molecules M. S. Butler, Nat. Prod. Rep. 2005, 22, 1620. Plants (300.000 – 400.000 species, 10% investigated) (C) HKD 2013 DRUG DISCOVERY Natural molecules M. S. Butler, Nat. Prod. Rep. 2005, 22, 1620. Bacteria, fungus (> 1.000.000 species, but <10% bacteria , 5% fungus investigated) Marine sources: algae, corals, sponges (500. 000 species, less-investigated) (C) HKD 2013 DRUG DISCOVERY Nature-inspired molecules Inspiration from receptor’s natural ligand Inspiration from enzyme’s natural substrate (C) HKD 2013 . COMPOUND. 9 18 03: Isolation of morphine from opium poppy by Friedrich Serturner. 9 18 19 -18 20: Isolation of strychnine, caffeine, quinine and colchicine by Pelletier and Caventou End of 19 th century. formulable) (C) HKD 2 013 DRUG DISCOVERY AND DEVELOPMENT OPTIMIZATION PHASE M. McCoss, Organic chemistry in drug discovery, T. A. Baillie Science 2004, 303, 18 10 (C) HKD 2 013 DRUG DISCOVERY AND. 2005, 22, 16 20. Frogs Fishes Snakes (C) HKD 2 013 DRUG DISCOVERY Natural molecules M. S. Butler, Nat. Prod. Rep. 2005, 22, 16 20. Plants (300.000 – 400.000 species, 10 % investigated) (C) HKD 2 013 DRUG