1. INNOVATORS 2010 “Changes of Strategies in Drug Discovery” The PWSC Research Achievement Award Christian R. Noe University of Vienna

2. ABSTRACT Over the decades many new strategies, concepts, methods and tools have been brought up in drug discovery. This presentation will demonstrate that many of those have remained valid and have developed into a broad repertoire of important elements required for successful drug research. Young Innovators 2009

3. INTRODUCTION Five different elements of drug discovery will be presented and their changing role in drug research shortly described: Benzene thiophene bioisterism Chirality Oligonucleotides Pharmaceutical (bio)analysis In vitro Models of the Blood Brain Barrier Young Innovators 2009

4. BENZENE THIOPHENE BIOISOSTERISM From “me too concept” to circumvene patents arriving at (hopefully) somewhat better drugs To element of the toolbox for lead optimisation Now: versatile tool for the design of “individualised” drugs Young Innovators 2009

5. BENZENE THIOPHENE BIOISOSTERISM - NSAIDs Piroxicam Long acting Lornoxicam Very short acting Tenoxicam Very long acting

6. BENZENE THIOPHENE BIOISOSTERISM Young Innovators 2009 Example for lead optimisation (glycine antagonists)

7. CHIRALITY From unresolved problem in the art of synthesis To formal requirement of drug quality Now: tool for mechanistic studies of drug- target-interaction on the molecular level Young Innovators 2009

8. CHIRALITY Young Innovators 2009 Lactols as tools in synthesis of enantiomers Highly distereoselective acetal formation

9. N + O O OH R R O O OH S R N + O O O H S S N + O O OH CH 3 R S 12 34 CH 3 CH 3 CH 3 CH 3 CH 3 N + CH 3 CH 3 Dexpironium is the R,R-isomer. Its dissociation from the M3-receptor is much slower than that of the other isomers A M3 ANTAGONIST WITH KINETIC SUBTYPE SPECIFICITY

10. OLIGONUCLEOTIDES From “small brother” of gene therapy To indispensable tool in studies of cellular function Now: Lead structures for a “parallel world of therapeutics” addressing the genomic level. Young Innovators 2009

11. ZWITTERIONIC OLIGONUCLEOTIDES

12. NF P MR P P P SM DNA mRNA TS AS ODN siRNA NR NUCLEIC ACID THERAPEUTICS The next big thing to come! (Scrip Magazine ) Cell Answer A parallel world of therapeutic intervention will open up! Block the receptor or prevent its expression!

13. PHARMACEUTICAL (BIO)ANALYSIS From traditional pharmaceutical task To driver in development of bio-analytical methods Now: Tools in pharmaceutical systems biology to assess details of drug action on cellular level Young Innovators 2009

14. A B F D 3, 8 4, 0 4, 2 4, 4 4, 6 4, 8 5, 0 5, 2 5, 4 5, 6 5, 8 6, 0 6, 2 6, 4 6, 8 7, 0 7, 2 7, 4 7, 6 7, 8 8, 0 8, 2 8, 4 8, 6 8, 8 9, 0 9, 2 9, 4 9, 6 9, 8 6, 6 theoret. location of h-EPO 2D – GEL ELECTROPHORESIS OF EPO (A) – DIGITAL SUMMARY AFTER CARBOHYDRATE CLEAVAGE (B, D, F)

15. EFFECTS OF OBLIMERSEN ON THE PROTEOME OF 607B MELANOMA CELLS Identification of differentially regulated proteins by MALDI-rTOF-MS % Int. VPADTEVVCAPPTAYIDFAR [MH+]: 2193.29

16. PROTEIN NETWORK PROTEIN NETWORK RELATED TO „OFF-TARGET“ EFFECTS OF THE PHOSPHOROTHIOATE DRUG CANDIDATE OBLIMERSEN

17. in vitro BLOOD BRAIN BARRIER MODELS From drug transport studies To studies on tightness and function Now: Important physiological system and immediate target in drug therapy above all in the field of neurodegeneration Young Innovators 2009

18. in vitro BLOOD BRAIN BARRIER MODELS Multicapillary model Tricapillary model Transwell model - Use of primary cells

19. THE ATPS LADDER – A BBB TIGHTNESS MARKER CE Separation of APTS-Glukose, - Maltose, - Dextrane 1500, - Dextrane 6000

20. 170 kDa 130 kDa 95 kDa 72 kDa 55 kDa 43 kDa 26 kDa ABC Western blot analysis of the expression of NMDA NR-2A in two ECV304 samples [A,C]. Lysate of mouse cerebellum was used as a positive control [B]. The role of NMDA receptors in the BBB is still unclear! STUDIES ON (DYS)FUNCTION OF THE BBB NMDA receptor expression in the BBB endothelium

21. RESULTS Studies on benzene-thiophene-bioisosterism have directly contributed to the discovery of three drugs on the market (brotizolam, tenoxicam and lornoxicam). Studies on stereochemistry based modulation of receptor kinetics have resulted in a clinical drug candidate (dexpironium). Young Innovators 2009

22. RESULTS Oligonucleotide (ON) design has revealed the potential of the important 2´-modification. Application of proteomics has allowed to assess details of drug action on cellular level. As a first result it has led to the detection of the sequence independent apoptotic effect of the phosphorothioate-modification of ONs. Young Innovators 2009

23. RESULTS Work on the blood brain barrier has resulted in an effective tool to assess the density of the BBB. Young Innovators 2009

24. DISCUSSION The Tasks of a scientist: „Ideological“ „Technological“ „Sociological“ „Ideological“ Progress of the research field: „From hypothesis to knowledge“ Themes as described before, above all work on chirality (stereoelectronic effects), thiophene chemistry, oligonucleotides and blood brain barrier (dys)function Young Innovators 2009

25. ADDITIONAL TASKS OF A SCIENTIST “Technological” Transfer of knowledge into society: „From knowledge to innovation“ Discovery of new APIs (active compounds), API technology – an undeveloped field of pharmaceutical science and education “Sociological” Service to society: „From knowledge to advice“ Work with UNIDO - „Multi Purpose Pilot Plant Concept“, President of EUFEPS; Chair of the Innovative Medicines Initiative (IMI-JU), above all: service as University Professor Young Innovators 2009

26. ACKNOWLEDGMENTS Thanks to the University of Technology of Vienna, the ETH Zürich, the Goethe-University Frankfurt and the University of Vienna, places, where I received my scientific education and/or was part of the collegium Thanks to my teachers, colleges and friends for discussions, help and inspiration Thanks to many co-workers, with whom I have had the pleasure to share adventures and excitement of research Thanks to my family Young Innovators 2009

27. BIOS/CONTACT INFO Christian.Noe@univie.ac.at Young Innovators 2009