the safety related attrition challenge: a medicinal
TRANSCRIPT
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Steve SwallowAstraZeneca R&D, Global Safety Assessment
The Safety Related Attrition Challenge: A Medicinal Chemists Perspective
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Introduction � Pharmaceutical industry facing ever increasing challenge� Rising costs & static productivity
50
75
100
125
150
175
200
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
IND
EXED
TO
199
9
R&D expenditure NME output
+ 74% R&D
- 37% NMEs
Source: CMR International (2010 FactBook) & IMS Health
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Reasons for Attrition
Kola et al, Nature Reviews Drug Discovery 2004, 3, 711
� Shift in attrition from DMPK to toxicology� No evidence of significant change in 2010
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Discovery Toxicology Investment Needed
Kola et al, Nature Reviews Drug Discovery 2004, 3, 711
� Reduction in DMPK related attrition achieved through:• Investment in discovery DMPK• Development of assays• Sharing of data and analysis• Communication – integration into project teams
Close scientific collaboration between DMPK & medchem
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AstraZeneca Safety Data Strategy
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A chemists view of toxicologyTarget Related
Toxicity
Toxicological outcome
Reactivity & bioactivation
Off Targetpharmacology
Physicochemicalproperties
Substructures Whole molecule property (Typically)
Chemistry Related Toxicity
NH
OO
NH
NH
S
NN
F
Experimental Plan
To mitigate risksChemist Toxicologist
DeeperunderstandingEarlier Hazard identification
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Earlier identification of chemical hazards
Reactivity & bioactivation
Off Targetpharmacology
Physicochemicalproperties
Substructures Whole molecule property (Typically)
Assays (Safety Assessment and DMPK)
In Silico approaches
Chemtox risk assessment
“Those who cannot remember the past are
condemned to repeat it.” George Santayana: Life of Reason, Reason in Common Sense, Scribner's, 1905, page 284
• SMARTS matching • QSAR models •Similarity based
methodsIn Silico approaches
Chemistry Related Toxicity
NH
OO
NH
NH
S
NN
F
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Structural Alerts� Multitude of sub-structural
alerts to be aware of� Reactive metabolites� Genotoxicity� Reactive structures� Toxic metabolites
FO
OHF
O
OH
OHO
OH
OOH O
OH
OOH
OH
OH
O
2-fluorocitrate 4-hydroxy-trans-aconitatepotent inhibitor of aconitase
Example:� Fluoroacetic acid is a known potent
rodenticide and human toxin� Lethal in man in 2-10mg/kg doses� Mechanism well understood –
inhibitor of tricarboxylic acid cycle
� Described in Stryer in 1980’sIntegrate structural alerts into design tools
� Still appearing to cause problems for medicinal chemists� Example: J. Med. Chem. 2008, 51,
4239–4252
N
OH
N O
N
FF
F
clinical candidate
N
OH
N O
N
F
FF
toxic via fluoroacetategeneration
“we were surprised to find mortality within 12 h
postdose in 2 of 3 rats in the
12 mg/kg group.”
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hERG: example of a mature target?� Withdrawals in late 1990s for risk of
Torsades de Pointes� E.g Terfenadine & Cisapride
� Identification of hERG as a leading cause of QTc prolongation
� ICH E14 guidelines in 2005 – introduced need for “thorough QT/QTc study”
� Significant investment in preclinical risk assessment and mitigation strategies
Routine assessment of hERG & other ion channels in AZ and other pharma
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hERG: example of a mature target?Less cardiac arrythmia liability over time
0%
20%
40%
60%
80%
100%
2004 2005 2006 2007 2008
Year Measured in Ionworks
Mea
sure
d hE
RG
IC50
> 10 μM3 to 10 μM< 3μM
Strategies to avoid well understood, many projects can avoid through early focus – evidence of improved compound design?
~60%
~73%
% in
hE
RG
IC50
bin
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Are we improving design against hERG?
~30% fewer compounds with predicted hERG activity < 10�M since 2005
� Global QSAR Model:� Comparison of hERG predictions for 1st 10k compounds by year
74% > 10��M 78% > 10�M
200968% > 10�M
20072005
coun
t
Binned predicted pIC50
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� Project hERG Model� Sub-structure corrections� Interpretable with respect to SAR� Lipophilicity Model for ClogD
� Better performance than global Models for some projects
4
4.5
5
5.5
6
Herg
_pIC
50 A
ctua
l
4.0 4.5 5.0 5.5 6.0Herg_pIC50 Predicted
Project Herg Model
Working with hERG in Projects
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Molecular Matched Pairs
XR YRP Probability for given
transformationX to Y
+ive-iveneutral
XR1
XR2
XRn
But context may be important
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Matched Molecular Pairs & hERG
J. Chem. Inf. Model. 2010, 50, 1872GSK and Univ. Sheffield
+ive-iveneutral
H>>OCH3
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Molecular Matched Pairs
XR YRP Probability for given
transformationX to Y
+ive-iveneutral
XR1
XR2
XRn
But context may be important
Ref: Griffen, E. Future Medicinal Chemistry 1:405-408 (2009)
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Proteins
QueryQueryMolecule
• Vast number of ligand-protein interactions described in literature
• Molecular structures & associated activity available and searchable in-silico
GPCR-x antagonists
Protease-z inhibitors
Kinase-yinhibitors
Predictive Secondary Pharmacology
• Identification of compounds similar to a query molecule canidentify potential off targets
Standard Target Panel
Inclusion of additional screening targets can lead to earlier risk assessment
Additional screening targets
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AZ1234• Acylcyanamide
substructure looks potentially reactive • Speculated protease
inhibition?
Acyl cyanamide
OH
O
M2N
O
HN
M1
M3
M4
M5
M6
M7
• AZ compound shown to cause cataracts in rats
• Circulating metabolites observed
• Q. Could there be an association between metabolites and cataract formation?
Use of PSP in problem solving
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N
O
HNM1
PSP search• Conducted on acyl cyanamide substructure
RN
O
HN
Where R is any carboncontaining group
WO 03/086325 A2Cyanamides useful as reversible inhibitors of cysteine proteasesCyanamide derivative as Cathepsin K, Cathepsin S, Cathepsin F, Cathepsin L and Cathepsin B inhibitor: Useful in the treatment of rheumatoid arthritis, multiple sclerosis, autoimmune diseases, osteoporosis, asthma, Alzheimer's disease, atherosclerosis and endometriosis
US 6878706 B1Cyanamides useful as reversible inhibitors of cysteine proteases
US 20080267917 A1N-functionalized amides as hepatitis c serine protease inhibitors
Results (Selected examples) Conclusions• Potential as cysteine and
serine protease inhibitors highlighted
• All peptidomimeticinhibitors
• Structural & biological relevance uncertain
Use of PSP in problem solving
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Results (cont’d)
• Benzoylcyanamide highlighted as closest analogue
J. Med. Chem. , 1986, 29 (10) 1922-1929Acyl, n-protected alpha-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide
N
O
HN
benzoylcyanamide
OH
O
M2N
O
HN
M1
AZ1234
cyanamide
O
OHNH2 N
benzoic acid
+
• Benzoylcyanamide is a prodrug of cyanamide
• Cyanamide inhibits aldehydedehydrogenase (ALDH) in-vivo in rats• Prodrug provides sustained activity
compared with cyanamide (reduced acute effect)
• Cyanamide inhibition of ALDH implicated in formation of cataracts in rats lenses in-vitro• Journal of toxicology and environmental
health. Part A (2009), 72(9), 577-84
+ NH2 N?
• Formation of cyanamide consistent with AZ1234 metabolism
Use of PSP in problem solving
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Availability of suitable data sets� Limited in-vitro data sets of suitable size� In-vivo safety data not organized for structure activity
relationship determination
Data repurposing a significant but necessary challenge
Increasing desire for precompetitive data sharing
Reports Structured data – observations aligned to exposure Analysis
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Availability of suitable data sets� Biowisdom Collaboration
� Metadata from text mining available alongside biological & chemistry data
� Some challenging questions now readily searchable...� Example. Find compounds that have activity X that
have a 1 month rat study
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Physicochemical Properties and toxicity
� High lipophilicity associated with higher probability of poor outcomes against various relevant endpoints
� Pfizer ‘rule of 3/75’ basedon in-vivo outcomes Bioorg. Medchem. Lett. 2008, 18, 4872
� Recent focus on minimizing lipophilicity contribution to potency in LG and LO
Review:M . J. Waring, ExpertOpinion on Drug Discovery (2010), 5(3), 235-248
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Phospholipidosis� Generally considered an adaptive response
� Some compounds display adverse effects pre-clinically & in humans
Are phospholipogenic compounds associated with more toxicities than non-phospholipogenic compounds?
Predictive in-silico models and assays available
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Lung
Bone
Mar
row
Lym
ph N
ode
Splee
n
Adre
nal G
land
Repr
oduc
tive O
rgan
s
Thym
us
Kidn
ey
Liver
0102030405060708090
100 Non-PhospholipogenicPhospholipogenic
% N
on P
LD F
indi
ngs n = 46
n = 55
Phospholipidosis
Phospholipogenic compounds show more non-PLD related findings in all organs despite lower exposure
Note: Exposures greater in non-
phosphilipogenic set
� Study Report text mining
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‘All things are poison, and nothing is without poison; only the dose permits something not to be poisonous’ - Paracelsus – 1493-1541
From Pfizer: Bioorg. Medchem. Lett. 2008, 18, 4872
� Exquisite potency and PK to work in this area
� Greater exploitation of biochemical efficiency?� Kinetics and PD
Importance of Dose and Exposure
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� A review of biochemical mechanisms of FDA approved NMEs 2001-2004 highlights� 80% utilize secondary mechanisms
in addition to initial mass action binding
� Slow dissociation & irreversible 25%
� For reviews see� Curr. Opin. Drug Disc. & Dev. 2009, 12, 31� Curr. Opin. Drug Disc. & Dev. 2009, 12, 488
The importance of binding kinetics and residence time
Potential to minimize exposure through extended PD
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Summary
� Significant investment in Discovery Toxicology needed to improve safety related attrition rate
� Repurposing of data a significant but necessary challenge� Precompetitive sharing of data sets should offer significant
value in some areas� In silico approaches are showing value in improving
compound design & safety hazard identification� Physicochemical property control important – mechanistic
understanding is limited� Earlier understanding of biochemical mechanisms and
kinetics may offer pharmacodynamic opportunities
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� PLATO & PSP� Scott Boyer� Tobias Noeske� Ola Engvist� Mike Rolf� Catrin Hasselgren
� PLD� Paul Ciaccio� Jim Damewood� Linda Barone� James Fikes
� WizePairZ & Application� Dan Warner� Ed Griffen� Stephen St Gallay
� Data Repurposing� Biowisdom� Sherri Mattis� Dave Cook
� IDEAL� Andrew Poirrette� John Cumming
Acknowledgements
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Extras
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� Mechanism of cyanamide inhibition?Chem. Res. Toxicol. 2005, 18, 790
Nitroxyl generated from cyanamide
Molecular and cellular proteomics, 2009, 85, 887
Nitroxyl implicated in protein modification via cysteine
Disulfide or sulfinamide formation
Response likely dependent on cellular location scavenging mechanisms etc
NH2
N
Catalase/H2O2 NH
N
OHC
N
cyanide nitroxyl
NO
H+ + H+
SR S
RRSH
RS
NH2
O
orHNO
Credible hypothesis generated, new structural alert?
Use of PSP in problem solving
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� Cyanamide inhibition of ALDH has been implicated in cataract formation in rats in-vitro
Journal of toxicology and environmental health. Part A (2009), 72(9), 577-84
ALDH1A1Oxidative
stressH
OH
O
4-hydroxynon-2-enalToxic
OHOH
O
4-hydroxynon-2-enoc acidNon-toxic
• Toxic lipid derived aldehydes formed by oxidative stress• 4-hydroxynon-2-enal (HNE) formation leads to lens damage• Detoxified by ALDH1A1• Inhibition of ALDH1A1 leads to increased toxicity
Credible hypothesis generated, new structural alert?
Use of PSP in problem solving
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Phospholipidosis� Study Report text mining