Drug Metabolism and Toxicity
58
Drug Metabolism and Toxicity Edna Mao Group Meeting Literature Talk October 13 th , 2021
Transcript of Drug Metabolism and Toxicity
Drug Metabolism and Toxicity
Edna MaoGroup Meeting Literature Talk
October 13th, 2021
Drug discovery and development
Discovery Preclinical development
Clinical trials
FDA review
Approved drug
> 5000 compounds
250 compounds
5 compounds 1 compound
Image credit: Ian B. Perry
Reasons drugs fail in the pipeline
Most common reason for failures in drug
discovery attributed to pharmacokinetic properties
Harmful toxicity another major concern in
drug development
Van de Waterbeemd, H.; Gifford, E. Nat. Rev. Drug. Discov. 2003, 2, 192–204.
Pharmacokinetics
The study of the bodily processes that affect the movement of drugs across the body
Fundamentals of pharmacokinetics
Absorption
Route of administration
Bioavailability
Distribution
Transfer of drug through body by bloodstream
Sites of accumulation
Metabolism
Biotransformation pathways
Mechanism of detoxification/active species formation
Excretion
Method and rate of drug clearance from body
Outline
Introduction to drug metabolism
Common biotransformations
Applications to drug design
Designing around metabolism
Metabolism-induced toxicity
Mechanisms of adverse reactions Reactive intermediates and
structural alerts
Applications to drug design
Designing around drug-induced toxicity Challenges in predicting adverse effects
Outline
Introduction to drug metabolism
Common biotransformations
Applications to drug design
Designing around metabolism
Metabolism-induced toxicity
Mechanisms of adverse reactions Reactive intermediates and
structural alerts
Applications to drug design
Designing around drug-induced toxicity Challenges in predicting adverse effects
Introduction to drug metabolism
Xenobiotic metabolism
The chemical alteration of non-endogenous compounds within the body
The early studies of metabolism
1841-1842
Ure and Keller independently ingest benzoic acid
Observed compound in urine in “copious amounts”
Compound similar to benzoic acid, but contained nitrogen
1845
Compound identified by Dessaignes as hippuric
acid (glycine–benzoic acid conjugate)
Glycine conjugation
first metabolic reaction to be described!
1848-1893
Methylation, aromatic oxidation, and conjugation
reactions characterized
Mechanisms considered “absolutely puzzling”, a “biochemical curiosity”
1945
Lipmann elucidates role of coenzyme A in acetylation reactions
Discovery wins Nobel
Prize in Medicine in 1953
Early 1900’s
Metabolism found to occur primarily in liver
Liver microsome
isolated in 1943 by Claude
1960’s
Discovery and characterization of
cytochrome P450’s and their role in drug
metabolism
1947
Richard Williams publishes “Detoxification mechanisms”, solidifying
drug metabolism as a defined field of study
King, R. S. Drug Metabolism Handbook: Concepts and Applications.; John Wiley & Sons, 2009; pp 3–9.
First pass metabolism
Metabolism by gastrointestinal enzymes
Orally administered drug
Metabolism by gut bacterial enzymes
All orally administered drugs pass through portal vein into liver before distribution to
the rest of body
Fraction of dose enters bloodstream
The concentration of orally administered drugs is greatly
reduced by “first pass metabolism” before reaching systemic circulation
Phase I and II biotransformations
Ionescu, C.; Caira, M. R.; Drug Metabolism: Current Concepts.; Springer, 2005.
Phases of drug metabolism
Phase 1: Modification
Introducing functional handles to drug
Phase 2: Conjugation
Attaching highly hydrophilic groups
Drug molecule Lipophilic,
not excretable
Excretion Bile, urine
Modified compound Polar, hydrophilic
Metabolism
Phases of metabolism
Initial modifications to drug molecules
Adding or uncovering reactive functional groups
Mostly facilitated by CYP enzymes in liver
Phase I metabolism
Conjugation of polar functional groups, usually resulting in deactivation
Facilitated by wide variety of transferase
enzymes
Conjugated molecules are recognized by transporters and excreted
Phase II metabolism
Cytochrome P450s
N
N
N
N
Me
Me
MeMe
Fe
O HO OOH
Heme B
Superfamily of heme-containing monooxygenase enzymes
R R
H
CYPO2 H+
R R
OHH2O
NADPH NADP+
+ + +
Ionescu, C.; Caira, M. R.; Drug Metabolism: Current Concepts.; Springer, 2005.
The Cytochrome P450-dependent mixed-function oxidase system
In human microsomes, P450s found on in mitochondrial and
endoplasmic reticulum membranes
CYP enzymes responsible for 75% of metabolism
Other enzymes that facilitate metabolism
Flavin-containing monooxygenases (FMO) Alcohol dehydrogenase (ALD)
Aldehyde oxidases (AO) Monoamine oxidases (MAO)
Ionescu, C.; Caira, M. R.; Drug Metabolism: Current Concepts.; Springer, 2005.
Phase I biotransformations - Oxidations at carbon centers
Aromatic hydroxylation Epoxidation
Aliphatic hydroxylation
R R
OH
CYPR R
O
CYP
R R
H
R R
OHCYP
R OHADH/ALDH
R OH
O
Alcohol oxidation
Dehalogenation
Halothane
Br
ClCYPF
FF
Br
ClF
FF
OH – HBrCl
F
FF
OH2O
OHF
FF
OH
Ionescu, C.; Caira, M. R.; Drug Metabolism: Current Concepts.; Springer, 2005.
Oxidative dehalogenation
Phase I biotransformations - Oxidations at heteroatoms
N-dealkylation
O-dealkylation
RN
CH3
R
RN
H
RCYP
viaR
NR
OH
RO
CH3 RO
H
CYP
viaR
O OH
Ionescu, C.; Caira, M. R.; Drug Metabolism: Current Concepts.; Springer, 2005.
N-oxidation
Deamination
FMORN
RN
OR
R RR
MAOR
RNH2 H
O
Responsible for the inactivation of endogenous neurotransmitters
Targeted by class of antidepressant and anti-anxiety medications known as “MAO
inhibitors”
Phases of metabolism
Initial modifications to drug molecules
Adding or uncovering reactive functional groups
Mostly facilitated by CYP enzymes in liver
Phase I metabolism
Conjugation of polar functional groups, usually resulting in deactivation
Facilitated by wide variety of transferase
enzymes
Conjugated molecules are recognized by transporters and excreted
Phase II metabolism
Phase II conjugations: glucuronidation
Glucuronidation
ROH
UDP-glucuronosyl transferase (UGT)R
OO
OHO
HOHO
OH
UDP-Glucuronic acid
O
OHO
HOHO
OH O PO
OHO P
O
OHO O N
NH
O
O
HO OH
Ionescu, C.; Caira, M. R.; Drug Metabolism: Current Concepts.; Springer, 2005.
Phase II conjugations
ROH
Sulfotransferase (SULT)R
OS
O
O
OPAPS
(3′-Phosphoadenosine-5′-phosphosulfate)
RNH2
N-acetyltransferaseR
HN
acetyl-CoAMe
O
Glutathione conjugation
O SO
OO P
O
OO O N
O OHPO
OO
N
NN
NH2
Reactive electrophile O
HN
OH
OS
NH
NH2
HO
O OGlutathione transferase (GST)
Glutathione (GSH)
OR
R
ROH
R
Sulfation
Acetylation
Ionescu, C.; Caira, M. R.; Drug Metabolism: Current Concepts.; Springer, 2005.
Phases of drug metabolism
Phase 1: Modification
Introducing functional handles to drug
Phase 2: Conjugation
Attaching highly hydrophilic groups
Drug molecule Lipophilic,
not excretable
Excretion Bile, urine
Modified compound Polar, hydrophilic
Metabolism
Implications of metabolism on drug design
Drugs need to reach their targeted site and remain in the system for a meaningful amount of time in order to elicit the desired pharmacological effects.
Pharmacokinetic properties which are impacted by metabolism:
Clearance Half life
Bioavailability
Prodrugs
Prodrugs: a class of drugs administered in a pharmacologically inactive form, which upon administration is enzymatically converted into its active form in vivo
Prodrug strategy can overcome challenges in :
Absorption Route of administration
Low bioavailability
Case study: Sofosbuvir (Pharmasset/Gilead)
Approved in 2013 for hepatitis C WHO List of Essential Medications
Nucleotide prodrug (ProTide)
O N
HN
O
O
MeO
Sofosbuvir
FHO
PO
OPh
NH
MeO
O
Me
Me
The ProTide approach: Sofosbuvir
Nucleoside analogue drugs tend to suffer from low potency due to slow first phosphorylation
Active form of drug
Nucleosides delivered as the monophosphate suffer from poor absorption and bioavailability due to charged phosphate
O N
HN O
O
MeHO
Nucleoside Nucleoside monophosphate
FHO
O N
HN O
O
MeO
FHO
PO
OO
slow
Nucleosidekinase
Nucleoside triphosphate
O N
HN O
O
MeO
FHO
PO
OOfast
PO
O O
P OOO
Rautio, J.; Meanwell, N. A.; Di, L.; Hageman, M. J. Nat. Rev. Drug. Discov. 2018, 17, 559–587.
Rautio, J.; Meanwell, N. A.; Di, L.; Hageman, M. J. Nat. Rev. Drug. Discov. 2018, 17, 559–587.
Phosphate group masked
Effectively distributed to hepatocyte cytosol (cells expressing high levels of CTSA/CES1)
ProTide hydrolyzed intracellularly (no metabolite detected in plasma)
The ProTide approach: Sofosbuvir
O N
HN
O
O
MeO
Sofosbuvir
FHO
PO
OPh
NH
MeO
O
Me
Me
CTSA/CES1
ester hydrolysis
O N
HN
O
O
MeO
FHO
PO
OPh
NH
MeHO
O
Sofosbuvir triphosphate
Recognized by HCV NS5B polymerase
Incorporated into RNA strand, leading to chain
growth termination
UMP-CMP kinase,NDPK
The ProTide approach: Sofosbuvir
Rautio, J.; Meanwell, N. A.; Di, L.; Hageman, M. J. Nat. Rev. Drug. Discov. 2018, 17, 559–587.
O N
HN
O
O
MeO
FHO
PO
OPh
NH
MeHO
O
–PhOH O N
HN
O
O
MeO
FHO
POH
N
O
O
Me
H2O HINT1 O N
HN O
O
MeO
FHO
P
O
OOO N
HN
O
O
MeO
FHO
PO
NH
MeHO
O O
O N
HN O
O
MeFHO
OPOPOO
OPO
OO O O
Lessons learned from metabolic studies
Information from metabolic studies can be used for rational drug design
Case study:
Ezetimibe (Schering-Plough/Merck) Approved in 2002 for hypercholesterolemia 125th most prescribed medication in 2018
Clader, J. W. J. Med. Chem. 2004, 47 (1), 1–9.
N
O
OMe
OMe
Lead compound: SCH-48461
Clader, J. W. J. Med. Chem. 2004, 47 (1), 1–9.
N
O
OMe
OMe
Lead compound: SCH-48461
Control group showed no decrease in plasma cholesterol until dosed with compound in week 3
Cholesterol-fed hamsters dosed with 1 mg/kg compound displayed a lower total plasma
cholesterol level Dosed group showed increase in plasma
cholesterol when dosing stopped at week 3
Case study: the development of Ezetimbe
Initial results with cholesterol-fed hamsters showed promising efficacy
Case study: the development of Ezetimbe
Rosenblum, S. B., et. al. J. Med. Chem. 1998, 41 (6), 973–980. Clader, J. W. J. Med. Chem. 2004, 47 (1), 1–9.
N
O
OMe
OMe
Lead compound ED50 = 2.2 mg/kg/day
N
O
OH
OMe
Metabolite isolated from bile (19)
Compound is rapidly metabolized in vivo, resulting in poor half life
Relatively high dose needed
Hamsters fed 14C cholesterol
14C cholesterol levels in plasma measured
Demethylated metabolite accounted for majority of
activity
Case study: the development of Ezetimbe
Rosenblum, S. B., et. al. J. Med. Chem. 1998, 41 (6), 973–980. Clader, J. W. J. Med. Chem. 2004, 47 (1), 1–9.
N
O
OMe
OMe
Lead compound ED50 = 2.2 mg/kg/day
N
O
OMe
OMe
OH
(S)-benzylic hydroxylation ED50 = 0.9 mg/kg/day
2x more potent than lead 5x more potent than (R)-hydroxylation
N
O
OMe
OMe
HO
C3 Aryl hydroxylation -16% LCE @ 50 mg/kg/dayLarge decrease in activity
N
O
OMe
OH
N-Aryl hydroxylation -78% LCE @ 50 mg/kg/daySlight decrease in activity
SAR studies
Case study: the development of Ezetimbe
Rosenblum, S. B., et. al. J. Med. Chem. 1998, 41 (6), 973–980.
N
O
OMe
OMe
SCH-48461
Unproductive sites of metabolism
Productive sites of metabolism
N
O
OH
F
OH
F
Ezetimibe
Metabolism blocked
Pre-metabolized
Monkey0.2 0.0005
ED50 (mg/kg)
Hamster2.2 0.04
Dog0.1 0.007
Outline
Introduction to drug metabolism
Common biotransformations
Applications to drug design
Designing around metabolism
Metabolism-induced toxicity
Mechanisms of adverse reactions Reactive intermediates and
structural alerts
Applications to drug design
Designing around drug-induced toxicity Challenges in predicting adverse effects
Adverse drug reactions (ADRs)
Type B (idiosyncratic ADRs)
Not associated with primary pharmacology, mechanism usually not understood
Does not occur at any dose for most people
Poor correlation with animal models
Often not detected until drug has been exposed to a
large population of patients
Attia, S. M. Oxid. Med. Chem. Longev. 2010, 3 (4), 238–258.
Adverse drug reaction:
a response to a drug that is noxious, unintended and occurs at doses normally used in man
Type A
Associated with primary pharmacology of drug
Usually detected in animal models/clinical trials
Can be mitigated through dose adjustments
Bioactivation to reactive metabolites
Drug moleculeDetoxified/deactivated metabolite
Metabolism
Bioactivation to reactive metabolites
Reactive metabolite
Drug moleculeDetoxified/deactivated metabolite
Bioactivation is usually the initial event in most drug-induced toxicities
Metabolism
Mechanisms of adverse reactions
Drug molecule
Metabolism
Reactive intermediate
Covalent binding
DNA Essential cell protein Autologous macromolecule
Mutagenesis, cancer
Cell death, necrosis
Immune response, hypersensitivity
Enzyme bindingEnzyme deactivation
Mechanisms of adverse reactions
Drug molecule
Metabolism
Reactive intermediate
Covalent binding
DNA Essential cell protein Autologous macromolecule
Mutagenesis, cancer
Cell death, necrosis
Immune response, hypersensitivity
Enzyme bindingEnzyme deactivation
Mechanism-based inhibition
General mechanism of C(sp3)–H hydroxylation
In some instances, a substrate can escape the oxygen-rebound step, binding CYP and leading to inactivation
Enzyme deactivated
Substrate escapes oxygen rebound step
SFeIV
O
Cys
R R
H
SFeIV
O
Cys
R R
H
SFeIII
O
Cys
HR
R
R R
OH
Oxygen reboundHAT
R R
Fe
Fe
R R
Reactive intermediate binds enzyme
Mechanism-based inhibition
De Montenallo, O.; Cytochrome P450: Structure, Mechanism, and Biochemistry. 3rd ed.; Springer, 2005.
Mechanism-based inhibition by paroxetine
HN
OO
F
O
Paroxetine
Approved in 1992 for use as antidepressant
74th most prescribed drug in 2018
Known to cause drug-drug interactions
Formed during metabolism
Strong inhibition ofCYP2D6 and CYP2B6
O
O
ROH
Prescribing guidelines warn that paroxetine is not to be taken with certain other drugs
De Montenallo, O.; Cytochrome P450: Structure, Mechanism, and Biochemistry. 3rd ed.; Springer, 2005.
O
O
RH
[Ox]–H+
O
O
Fe Fe
R OO
R
Mechanisms of adverse reactions
Drug molecule
Metabolism
Reactive intermediate
Covalent binding
DNA Essential cell protein Autologous macromolecule
Mutagenesis, cancer
Cell death, necrosis
Immune response, hypersensitivity
Enzyme bindingEnzyme deactivation
Classic example: drug-induced liver damage from acetaminophen
OH
NH
O
MeCYP2E1
O
N
O
MeGSH
OH
NH
O
Me
SNH
NH
O
COOHO
NH2HOOC
Acetaminophen Reactive quinoneintermediate Glutathione conjugate
Endogenous GSH levels depleted
Covalent binding to hepatic proteins Cell death,
liver damage
Most commonly used medication forpain and fever in the US and Europe
On WHO List of Essential Medicines
Leading cause of acute liver failure and drug overdoses in Western countries
Treatment of overdose may involve administratingof N-acetylcysteine (glutathione precursor)
Kalgutkar, A. S. J. Med. Chem. 2020, 63 (12), 6276–6302.
Classic example: Toxicity of benzene
O
O
1e-
O2
O2
Covalent binding
Quinone redox cycling generates reactive oxygen species
Bolton, J. L.; Dunlap, T. Chem. Res. Toxicol. 2017, 30 (1), 13–37.
OH
OH
Nuc
OH
OH
OH OHOH
O
O
OO
Benzene
CYP CYP Reactive quinone intermediates
The structural alert concept
Nelson, S. D. J. Med. Chem. 1982, 25 (7), 753–765.
Structural alerts (toxicophores): functional groups frequently found in drugs associated with adverse reactions
OR
NH
O
Me
R NH
ONH2 N
R
RR
ROR SR
RNO2
XR
Acetanilides Hydrazides Amines
Phenyl rings Heteroaromatics Nitroaromatics
Halogenated compounds
The structural alert concept
Nelson, S. D. J. Med. Chem. 1982, 25 (7), 753–765.
Structural alerts (toxicophores): functional groups frequently found in drugs associated with adverse reactions
Acetanilides Hydrazides Amines
Phenyl rings Heteroaromatics Nitroaromatics
Halogenated compounds
O
N
O
Me
R H
ON2 HR HR
OHN
R
R O X
R RN
O OHR SR
O
OHO
O
R O
Michael acceptors Alkylating/acylating agents Acylating agents, possible fluoride toxicity
Epoxidation leading to reactive intermediates Reactive oxygen species
NR
RR
or
Structural alerts as a method for identifying potential toxicity
Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Chem. Res. Toxicol. 2011, 24, 1345– 1410.
Survey of withdrawn drugs found structural alerts in
55 out of 68 drugs (80.8%)
The propensity to form reactive metabolites was
observed in 36 out of the 55 drugs (65%)
Drugs recalled due to idiosyncratic drug-induced liver injury
NH2HO
O
O
Br
Bromfenac Structural alerts: Aniline, bromobenzene
Withdrawn in: 1998
OHN
S
OMe
MeOH
MeMe
OO
Troglitazone Structural alerts: Thiazolidinedione, phenol
Withdrawn in: 2000Linked to 63 cases of liver-failure deaths
Hepatotoxicity is leading cause of idiosyncratic adverse drug reactions
O
N NN ClN
Et
NO
Nefazodone Structural alerts: N-aryl piperazine
Withdrawn in: 2004
S
SO
O
NH
O O
O
Me
O N
Me
Cl
Sitaxentan Structural alerts: 1,3-benzodioxole
Withdrawn in: 2010
Kalgutkar, A. S. J. Med. Chem. 2020, 63 (12), 6276–6302.
Assaying formation of reactive metabolites
Incubation of drug in liver microsome
Addition of appropriate nucleophile
(Glutathione, KCN)
Administration of radio labeled (3H /14C)
compounds
Isolate and quantify radioactive covalently bound proteins and
DNA
Evans, D. C., et. al. Chem. Res. Toxicol. 2004, 17 (1), 3–16.
Reactive metabolite trapping assays
O
R
NR
Reactive metabolites
HO
R
GSH
NR
CN
LC-MS analysis of adducts
Radiolabeling assays
Strategies for mitigating effects of structural alerts
Reports of hepatotoxicity,agranulocytosis
Reduce electron density of aromatic
rings
NH
Cl N
HO
CYP N
Cl N
O
Amodiaquine
Et2N Et2NAnalogues with improved safety profile
O’Neill, P. M., et. al. J. Med. Chem. 2009, 52 (5), 1408–1415.
Steric blocking of metabolically
active sites
NH
F
Ar
Et2N
NH
HO
Ar
HN
tBu
Kalgutkar, A. S., et. al. Bioorg. Med. Chem. Lett. 2009, 19 (6), 1559–1563.
NNH
N
N
O
Me
F
Me
Redesigned compound
Ames negative
Remove structural alert
Block metabolically labile sites
NN
N
N
R
O
Reactive intermediates observed
ClHO
OR
ClO
OR
Strategies for mitigating effects of structural alerts
NNH
N
N
O
Cl
5-HT2C (serotonin) receptor agonist(Pfizer)
Ames positive (mutagenic)
Investigated as bradykinin B1 antagonist
(Merck)
Incubation with human and rat liver microsome
N
N
RO
NR
N
NH
RO
NHRO
N
NH
RO
NHR
O
N
NH
RO
NHR
GS
N
NH
RO
NHRO
GS
N
NH
RO
NHR
GS
GSH
GSH
GSH
– H2O
Irreversible binding to liver microsomal proteins
Tang, C., et. al. Chem. Res. Toxicol. 2005, 18 (6), 934–945.
2,3-diaminopyridine moiety determined to be safety liability
Strategies for mitigating effects of structural alerts
N
NH
OCF3
NH
MeO2C
(Human bradykinin B1 inhibitor constant)
Tang, C., et. al. Chem. Res. Toxicol. 2005, 18 (6), 934–945.
NH
OCF3
NH
MeO2C
Simplify to ethylene diamineAdd conformational
constraint and hydrogen bonding capability
NH
OCF3
NH
MeO2C
O
hBK B1 Ki = 52 μM
Inactive
Bioisosteric replacement of structural alerts
Design principle:Replace 2,3-DAP with
nonaromatic linker
N
NH
OCF3
NH
MeO2C
hBK B1 Ki = 0.012 μM
Lead compound
Structural modification
Wood, M. R., et. al. J. Med. Chem. 2006, 49 (4), 1231–1234.
NH
OCF3
NH
MeO2C
O
Me
MeNH
OCF3
NH
MeO2C
ON
NH
OCF3
NH
MeO2C
120o 109o 116o
Thorpe-Ingolde effect allows for bioisosteric mimicry of 2,3-diaminopyridine bond angle
Large improvement in rat pharmacokinetic profile due to heightened metabolic stability
Bioisosteric replacement of structural alerts
Lead compound Redesigned
Challenges in predicting adverse effects
The ability to predict a priori whether drug bioactivation will lead to toxicity in humans is very limited
Challenges in predicting adverse effects
OH
NH
O
Me
Acetaminophen (APAP)
AMAP
NH
O
Me
OH
Hepatotoxic
Nonhepatotoxic
Dose normalized to give comparable levels of in vivo
covalent binding in mice liver
Adduction of “critical proteins” is required to cause organ toxicity
Not all protein binding is deleterious
Tirmenstein, M. A., Nelson, S. D. J. Biol. Chem. 1989, 264, 9814–9819.
]
Shortcomings of the structural alert concept
Driscoll, J. P.; Sadlowski, C. M.; Shah, N. R.; Feula, A. J. Med. Chem. 2020, 63 (12), 6303–6314.
Not every structural alert results in toxicity
53% of 108 of the most prescribed drugs in 2009 possessed structural alerts
Evidence of reactive metabolite formation in 41% of those cases
OOMe
Cl
N
S
Clopidogrel Thiophene structural alert
OOMe
Cl
N
SOCYP
OOMe
Cl
N
SO
O
OOMe
Cl
NCOOH
SOH
H2O P2Y12 receptor
OOMe
Cl
NCOOH
SS P2Y12
]
]
Shortcomings of the structural alert concept
Driscoll, J. P.; Sadlowski, C. M.; Shah, N. R.; Feula, A. J. Med. Chem. 2020, 63 (12), 6303–6314.
Not every structural alert results in toxicity
53% of 108 of the most prescribed drugs in 2009 possessed structural alerts
Evidence of reactive metabolite formation in 41% of those cases
Irreversible inhibition of
platelet aggregation
OOMe
Cl
N
S
Clopidogrel Thiophene structural alert
OOMe
Cl
N
SOCYP
OOMe
Cl
N
SO
O
OOMe
Cl
NCOOH
SOH
H2O P2Y12 receptor
OOMe
Cl
NCOOH
SS P2Y12
]
Shortcomings of the structural alert concept
Kalgutkar, A. S. J. Med. Chem. 2020, 63 (12), 6276–6302.
Not every IADR associated with a structural alert
“If medicinal chemists abstained from the
synthesis of phenyl ring-containing compounds
because the phenyl ring is considered as a
structural alert, humanity would be deprived of
countless life-saving drugs”Ximelagatran
Rejected for FDA approval in 2009 after clinical trials due to idiosyncratic drug-
induced liver injury
Cannot completely eliminate structural alerts
N
HN
O
H2N NOH
O HN O
OMe
Does not contain any known structural alerts
Lack of thorough
characterization
distinguishing critical
and noncritical proteins
Challenges in predicting adverse effects
Structural alert
analysis often inaccurate
Inter- and intra-species variation in drug metabolism
The ability to predict a priori whether drug bioactivation will lead to organ or immune toxicity is very limited
Drug discovery and development
Discovery Preclinical development
Clinical trials
FDA review
Approved drug
In-vitro studies
In-vivo studies Animal trials Human trials
General population
Higher accuracy of testing results Increasing stakes and cost of test subjects
Image credit: Ian B. Perry
Outline
Introduction to drug metabolism
Common biotransformations
Applications to drug design
Designing around metabolism
Metabolism-induced toxicity
Mechanisms of adverse reactions Reactive intermediates and
structural alerts
Applications to drug design
Designing around drug-induced toxicity Challenges in predicting adverse effects
