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1、Chemistry in Biomedicine,and Drug Discovery,Professor Ari Koskinen Helsinki University of Technology,11.03.2005,Ari Koskinen Laboratory of Organic Chemistry,Numberapprovedby,FDA,0,24,0,21,7,18,6,16,2,15,5,13,7,12,5,11,8,9,4,8,2,7,6,6,5,5,8,4,$/No.,New Chemical Entities vs. R&D Expedinture $ billions
2、,60,0,70,50 40 30 20 10 0,86 87 88 89 90 91 92 93 94 95 96 97 98 99,0,60 0,50 0,40 0,30 0,20 0,10 0,00,R&D Spending $ billions New molecular entities approved by FDA Ratio: $ / No.,Note: Ethical pharmaceuticals only. Expenditures worldwide by U.S.-owned research-based pharmaceutical companies,C&EN J
3、anuary 17, 2000, Food & Drug Administration, Pharmaceutical Research & Manufacturers of America: PhRMA Annual Survey 2000. Ari Koskinen Laboratory of Organic Chemistry,New Drug Development,Ari Koskinen Laboratory of Organic Chemistry,R 2001,Africa,Americas Europe,Asia-Pacific Australia,Middle East O
4、thers,Ari Koskinen Laboratory of Organic Chemistry,a,b,$ 1.7 bn (2003) per product is spent on,R&D Stage Synthesis/extraction Biological screening/ pharmacological testing Toxicology/safety Dosage formulation Clinical evaluation Process development for manufacturing/ quality control Regulatory Other
5、,% of spendinga 11.0 16.0 6.0 9.6 34.5 9.6 3.8 9.4,% of employeesb 12.9 18.3 7.8 11.6 24.3 10.3 4.8 10.0,Company financed R&D in US based on 1995 figures totalling $ 11.8 bn US scientific and professional personnel totaling 34, 784 employees Source: Pharmaceutical Research & Manufacturers of America
6、, Industry Profile 1997 2003 data: C&EN 2003, 81 (50), 8. Ari Koskinen Laboratory of Organic Chemistry,Market Exclusivity Times Decrease,Ari Koskinen Laboratory of Organic Chemistry,Development pipeline,Ari Koskinen Laboratory of Organic Chemistry,Top 10 Therapies,December 6, 2004 Volume 82, Number
7、49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Top 10 Products,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Mergers,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Off Patent,December 6, 2004 Volu
8、me 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Patents expiring,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Promising New Drugs,December 6, 2004 Volume 82, Number 49,pp. 18-29,Ari Koskinen Laboratory of Organic Chemistry,Diver
9、sity of Drug Structures,B,O,D,F,E,H,O,O G,Natural Products as Drug Leads O,Me MeO,O,NH,Cl HO,OMeO Me A1 Me O Cl O A,O,Me O HO NO2 Me,O O C O,Me MeO O O Me OH,Me OMe O O O OH OH,OH O G O OMe,O O H O O,O,O O HO,Me A2,OH,Me Me MeO,H,O O,O H OH O O,Me,Me,OMe,Everninomicin 13,384-1,Me Callipeltoside A,Cl
10、,inhibits proliferation of KB and P388 cells protects cells infected with HIV,O,16,OH,Me,Br,46,OMe 43,OH,OMe 33 O OH,N 29 O,O,24 O,O 1,N,O 9 O 5,HO,O,H,A O O Me,B O H Me C D H OH,E O OH H,HN I Me H H O Me O H F Me,Phorboxazole A,Azaspiracid causative agent for 1995 human poisonings by contaminated I
11、rish mussels Mytilus edulis Ari Koskinen Laboratory of Organic Chemistry,H,H,O,N,O,S,O O,N,N H O,N,N,H,O,H Me N,H,RCO N NMe S N CN NHH,O,O,N,O,O,Chemical Strategies in Drug Development Isolation Structure based synthesis,HO,N Rational Drug Design,O,OMe,HO O O,H Design based on Chemical Diversity Me
12、CO2H,Cl,N N N,O,N OH,Morphine -Lactams (antibiotics) Me O O Me N Me,Strychnine Br,split Tagamet Progesterone (anti-ulcer) Me O Me O O O O Me H,Quinine Valium Br(tranquilizer),Ari Koskinen Laboratory of Organic Chemistry,High Throughput Screening,Plants (500 000) Marine natural products (106),Inverte
13、brate natural products (109),Compound libraries Structure based design,Recombinant methods,Peptide libraries Peptidomimetic libraries,Ari Koskinen Laboratory of Organic Chemistry,Drug Development Paradigms Traditional Approach Clinical/preclinical Observations,Disease model,in vivo,LEAD,in vivo Stud
14、ies on pathophysiology Rational Approach in vitro,Disease gene,or in vivo,Validated target,in vitro,LEAD,design,Transgenic animals Ari Koskinen Laboratory of Organic Chemistry,Drug Development Paradigms TARGET IDENTIFICATION General,combinatorial libraries,LEAD GENERATION,Biased combinatorial librar
15、ies,LEAD OPTIMIZATION,Structural chemistry,DRUG CANDIDATE Ari Koskinen Laboratory of Organic Chemistry,Chemical Diversity,Basis set of 20,Units 203,Library Entities 8 000,(e.g. natural amino acids),204,160 000,205 Units,3 200 000 Library Entities,The number of different chemical entities, N = bx, wh
16、ere x = the number of steps, and b = number of different building blocks.,Basis set of 100 (e.g. carbohydrates),1003 1004 1005 Units 10003,1 Million 100 Million 10 Billion Library Entities 1 Billion,The problem of combinatorial synthesis is not that of making compounds, but that of finding ways to select and identify the compounds: One
