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INNOVATORS 2010
“Changes of Strategies in Drug Discovery”
The PWSC Research Achievement Award
Christian R. Noe
University of Vienna
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.
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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
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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
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BENZENE THIOPHENE BIOISOSTERISM - NSAIDs
NS
O O
OH O
NH
N
PiroxicamLong acting
NS
SCl
O O
OH O
NH
N
LornoxicamVery short acting
NS
O O
OH O
NH
N
S
TenoxicamVery long acting
BENZENE THIOPHENE BIOISOSTERISM
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NH
OH
OS
OCl
NH
OH
OS
NH
OH
OS
O
NH
OH
OSCl
Ki = 8300 nM
Ki = 570 nMKi = 270 nM
Ki = 20 nM
NH
OH
OS
OCl
Ki = 1.2 nM
Example for lead optimisation(glycine antagonists)
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
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CHIRALITY
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O
OSO2NR2 H
b
Ph
O
OSO2NR2 Ph
b
H
O
OSO2NR2
R2 = see table 1 and 2b = Me or tert. Butyl
BB-Form BA-Form
2
+
Lactols as tools in synthesis of enantiomers
Highly distereoselective acetal formation
N+
O
OOH
RR
O
OOH
S
R
N+
O
OOH
S
S
N+
O
OOH
CH3
RS
1 2
3 4
CH3
CH3
CH3
CH3
CH3
N+
CH3
CH3
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
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.
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O
O
O Base-1
O
O
Base-2
P
O
O
HO
O
O
Base-3O
HO
O
P
2'-O-Aminohexyl-L-lysyl DerivativeDNA
O
O
O Base-1
O
O
Base-2
P
O
O
HO
O
O
Base-3O
HO
O
P
ONH
O
O
O
NH2
NH2
O
NH2
NH2NH
O
NH2
NH2NH
ZWITTERIONIC OLIGONUCLEOTIDES
NF
P
MRP
PP SM
DNA
mRNA
TS
AS ODNAS ODNsiRNAsiRNA
NR
NUCLEIC ACID THERAPEUTICS
The next bigthing to come! (Scrip Magazine)
Cell AnswerCell Answer
A parallel world of therapeutic intervention will open up!
Block the receptor or prevent its expression!
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
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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)
EFFECTS OF OBLIMERSEN ON THE PROTEOME OF 607B MELANOMA CELLS
Identification of differentially regulated proteins by MALDI-rTOF-MS
% Int.% Int.
VPADTEVVCAPPTAYIDFAR [MH+]: 2193.29
PROTEIN NETWORK
PROTEIN NETWORK RELATED TO „OFF-TARGET“ EFFECTS OF THE PHOSPHOROTHIOATE DRUG CANDIDATE OBLIMERSEN
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
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in vitro BLOOD BRAIN BARRIER MODELS
Multicapillary model
Tricapillary model
Transwell model
- Use of primary cells
THE ATPS LADDER – A BBB TIGHTNESS MARKER
CE Separation of APTS-Glukose, - Maltose, - Dextrane 1500, - Dextrane 6000
170 kDa
130 kDa
95 kDa
72 kDa
55 kDa
43 kDa
43 kDa
26 kDa
A B C
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
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).
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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.
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RESULTS
• Work on the blood brain barrier has resulted in an effective tool to assess the density of the BBB.
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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
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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
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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
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