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1 Mitigation Strategies for Reactive Intermediates in Drug Discovery ew Perspectives in DMPK: Informing Drug Discovery Royal Society of Chemistry, London February 10-11, 2014 Thomas A. Baillie School of Pharmacy University of Washington Seattle, WA, USA

2 Chemically Reactive Drug Metabolites Role in Liver Toxicity Cancer Res., 7,, (1947) J. Pharmacol. Exp. Ther., 187, (1973) 2

3 Bioactivation and Liver Toxicity Acetaminophen (Paracetamol) (Quinone imine) D C Dahlin et al Proc atl Acad Sci USA (1984) D. C. Dahlin et al., Proc. atl. Acad. Sci. USA, 81, (1984) I. M. Copple et al., Hepatology, 48, (2008)

4 APQI Mediated Activation of rf2 rf2 GSH depletion Adduct formation Protein oxidation rf2 ARE Cell defence genes Keap1 rf2 Glutamate Cysteine Ligase Glutathione transferases AD(P)H quinone oxidoreductase Haem oxygenase Glucuronyl transferase Catalase Proteosomal proteolysis A. V. Stachulski et al., Med. Res. Rev., 33, (2013)

5 APQI Mediated Protein Damage A. V. Stachulski et al., Med. Res. Rev., 33, (2013)

6 Acetaminophen Induced Hepatotoxicity rf2 GSH depletion Adduct formation Protein oxidation rf2 Keap1 rf2 ARE Cell defence genes Glutamate Cysteine Ligase Glutathione transferases AD(P)H quinone oxidoreductase Haem oxygenase Glucuronyl transferase Catalase Proteasomal proteolysis f2d rf2 Defence Protein damage Increasing dose of acetaminophen. Kaplowitz, at. Rev. Drug Discov., 4: (2005); D. P. Williams, Toxicology 226: 1-11 (2006) A. V. Stachulski et al., Med. Res. Rev., 33, (2013)

7 P450-Mediated Quinoid Formation Toxicological Implications Target rgan Toxicity ote: Metabolism can often introduce / expose H / H functionalities xidative Damage (DA, Proteins)

8 Quinoid Precursors as Structural Alerts

9 Quinoid Precursors as Structural Alerts H H Cl Cl CYP HR GSH SG H HR Isoxazole F F H H Pyrazinone F CYP R 1 HR2 2 GSH R1 H SG HR2 1 2 Cl Cl Cl H C C CYP GSH GS H H 3 C Ar Pyridine H 3 C Ar H 3 C H H Ar C H 2 H 2 H S H CAr H 2 H 2 CYP GSH H S S H 2 CAr H 2 CAr SG H Thiophene Structural alerts must be supplemented by experimental data! S. D. elson, Adv. Exp. Med. Biol., 500; (2001); A. S. Kalgutkar et al., Curr. Drug Metab., 6: (2005)

10 Reactive Drug Metabolites Lessons Learned Some, but not all, reactive drug metabolites appear to be responsible for the toxicity of their parent compounds H H H High dose drugs (> mg/day) that generate reactive metabolites have the poorest safety record (high body burden of reactive metabolites?) H Bromfenac In most cases, the protein targets of reactive metabolites, and their toxicological relevance, are not yet known need for biomarkers Currently, it is not possible to predict whether a certain reactive metabolite will elicit a toxic response in vivo, although structural alerts can be helpful Practical risk mitigation strategy is to decrease exposure to reactive metabolites through structural re-design B. K. Park et al., ature Rev. Drug Discov., 10, (2011); A. V. Stachulski et al., Med. Res. Rev., 33, (2013)

11 Experimental Approaches for the Study of Experimental Approaches for the Study of Reactive Drug Metabolites

12 Assessing Formation of / Exposure to Reactive Drug Metabolites (A) bservation of time-dependent P450 inhibition in vitro - Implications for clinical drug-drug interactions (B) Formation of adducts with nucleophiles In vitro trapping experiments with GSH or C - (or radiolabeled counterparts) In vivo metabolic profiling studies (eg GSH conjugates in bile) - Invaluable in enabling rational structural re-design (C) Covalent binding studies with radiolabeled drug - Measures total burden of protein-bound drug residue - Helpful complement to trapping studies Timing: Late Discovery / Early Lead ptimization Goal: Structural re-design to minimize exposure to reactive metabolites 8

13 Elimination of CYP3A4 Time-Dependent Inhibition (TDI) Compound 1 Compound 1 formed a Metabolic Intermediate (MI) complex with CYP3A4 due to oxidation on the H 2 group In Compound 2, steric hindrance prevented H 2 oxidation, MI complex formation, and CYP3A4 inhibition Compound 2 W. Tang et al., Xenobiotica, 38, (2008) 14

14 MI Complex Formation from MC4R Agonists MI Complex CYP3A4 TDI o MI Complex (steric hindrance to -oxidation) Compound 2 W. Tang et al., Xenobiotica, 38, (2008)

15 Use of Glutathione Trapping to Guide Structural Modification rexin receptor antagonist lead o evidence of metabolic activation C. Boss et al., ChemMedChem, 5: (2010) 17

16 Covalent Binding as an Index of Metabolic Activation: The Discovery of Merck s CB-1 Inverse Agonist, Taranabant 1 (3900) G. A. Doss and T. A. Baillie, Drug Metab. Rev., 38, (2006) K. Samuel et al., J. Mass Spectrom., 38, (2003)

17 Evolution of Taranabant (CB-1 Inverse Agonist) W. K. Hagmann, J. Med. Chem., 51: (2008)

18 Reactive Drug Metabolites and Idiosyncratic Drug Toxicity it

19 Idiosyncratic Drug Toxicity Susceptibility to adverse drug reactions (ADRs) is a function of: (A) Chemistry of drug and its interaction with biological systems - n- and off-target pharmacology - Metabolic activation of accessible toxicophore (eg acetaminophen) - ormally dose-dependent, dependent predictable, reproducible in animals (B) Phenotype and genotype of patient - ot related to pharmacology of drug - Rare, no clear dose-response relationship, unpredictable, often not reproduced in animals ( idiosyncratic ) Idiosyncratic drug reactions can result from the sequence: Metabolic activation of parent Covalent modification of proteins ( chemical stress ) Presentation (in susceptible individuals) of adducted proteins to T-cells via specific HLA proteins Immune-mediated ADRs (often involving liver, skin, or circulatory system) G. P. Aithal and A. K. Daly, ature Genetics 42: (2010)

20 Metabolism-Dependent Abacavir Hypersensitivity J. S. Walsh et al., Chem.-Biol. Interact., 142, (2002); A. K. Daly and C. P. Day, Drug Metab. Rev., 44, (2012) C. C. Bell et al., Chem. Res. Toxicol., 26, (2013);. M. Grilo et al., Toxicol. Lett., 224, (2014)

21 ADRs: Reaction Frequency vs. Allele Frequency Reaction frequency Allele Abacavir Hypersensitivity HLA-B * Flucloxacillin Hepatotoxicity HLA-B * Carbamazepine SJS HLA-B * (Chinese) Carbamazepine Hypersensitivity i i HLA-A*3101 A* (Japanese) Carbamazepine Hypersensitivity HLA-A* (Caucasians) Lumiracoxib Hepatotoxicity HLA-DQA *0102 Ximelagatran Hepatotoxicity HLA-DRB *0701 Allele frequency Mallal, 2008; Kindmark et al., 2008; Daly et al., 2009; Chung et al., 2004; Williams et al., 2004; Levine et al., 2004; Kamali et al., 2009; McCormack et al., 2011.

22 Risk Factors for Drug-Induced Toxicity High clinical dose (>50 mg/day) Structural alert(s) for bioactivation Evidence of reactive metabolite formation In vitro trapping studies (GSH, C - ) Covalent binding to proteins Estimated reactive metabolite body burden in humans (>10 mg/day) In vitro time-dependent inhibition of CYP enzymes >5-fold shift in IC 50 Implications for drug-drug interactions In vitro inhibition of hepatic efflux transporters BSEP Mrp2 S. Verma and. Kaplowitz, Gut, 58, (2009); A. F. Stepan et al., Chem. Res. Toxicol., 24, (2011) S. Tujios and R. J. Fontana, ature Rev. Gastroenterol. Hepatol., 8, (2011)

23 Integrating Reactive Metabolite Studies with In Vitro Toxicology Assays An Integrated Approach to Risk Mitigation R. A. Thompson et al., Chem. Res. Toxicol., 25, (2012)

24 Conclusions There is compelling evidence that chemically reactive metabolites can mediate the serious adverse reactions to drugs and other foreign compounds However, the frequency and severity of such ADRs will depend upon a complex series of factors related to the host and the environment, as well as the reactive intermediate While avoidance strategies continue to be pursued during the lead optimization stage of drug discovery, integrated reactive metabolite hazard assessment strategies are now emerging, based on considerations of reactive metabolite body burden in conjunction with in vitro toxicity markers and preclinical in vivo safety testing The formation of reactive metabolites needs to be viewed as only one component of overall risk assessment in the development of new pharmaceuticals B. K. Park et al., ature Rev. Drug Discov., 10, (2011); A. V. Stachulski et al., Med. Res. Rev., 33, (2013)

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