Structural Alert/Reactive Metabolite Concept As Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxici
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REVIEW pubs.acs.org/crt Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States † † ‡ † || Antonia F. Stepan, ‡Daniel P. Walker, Jonathan Bauman, David A. Price, Thomas A. Baillie, Amit S. Kalgutkar,*, and Michael D. Aleo§ † ‡ Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism, and §Investigative Toxicology, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States Department) of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, 98195 bS Supporting Information ABSTRACT: Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examined as part of lead optimization efforts in drug discovery. Likewise, avoidance of “structural alerts” is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards associated with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addition, the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a molecule that contains a structural alert (RM positive or negative) a cause for concern? Could the molecule in its parent form exert toxicity? Can a low dose drug candidate truly mitigate metabolism-dependent and -independent idiosyncratic toxicity risks? In an effort to address these questions, we have retrospectively examined 68 drugs (recalled or associated with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochemical characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our analysis revealed that a significant proportion (∼78À86%) of drugs associated with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62À69% of these molecules. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochemical properties such as molecular weight, lipophilicity, etc. Approximately half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chemical architecture, and many were found to be RM-positive. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely associated with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addition, competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-positive drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our analysis suggests a need for a more integrated screening paradigm for chemical hazard identificationindrug discovery. Thus, in addition to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compound(s)) for lead compounds, effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compound liabilities. However, the prospective use of such data in compound selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiological mechanisms associated with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the associated “body burden” of the parent drug and its metabolites will remain an overarching goal in drug discovery. Received: April 25, 2011 Published: June 24, 2011 r 2011 American Chemical Society 1345 dx.doi.org/10.1021/tx200168d | Chem. Res. Toxicol. 2011, 24, 1345–1410 Chemical Research in Toxicology REVIEW ’ CONTENTS The precise mechanisms of IADRs remain unclear; however, it is believed that the majority of these reactions are caused by 1.0. Introduction 1346 immunogenic conjugates formed from the reaction of an electro- 2.0. Physicochemical Trends in Drugs Associated with philic reactive metabolite (RM) of a drug with cellular proteins IADRs 1355 resulting in direct cellular dysfunction or an immune response via 3.0. Structural Alert and RM Analyses for Drugs Recalled the formation of a hapten. Much of the groundwork of the RM Due to IADRs 1356 theory was laid by James and Elizabeth Miller who elegantly 3.1. Acidic Compounds 1356 demonstrated that the carcinogenic and hepatotoxic activity of 3.2. Basic Compounds 1361 aminoazo dyes resulted from their metabolic activation (also referred to as bioactivation) to RMs.3,4 Over the decades, bioacti- 3.3. Neutral Compounds 1362 vation of xenobiotics, including drugs, has been clearly implicated 4.0. Structural Alert and RM Analyses for Drugs with in causing DNA modification and mutations relevant to cancer.5 BBW 1363 The extension of the RM concept to idiosyncratic drug toxicity 4.1. Acidic Compounds 1364 was first provided from studies on the anti-inflammatory agent 6 4.2. Basic Compounds 1365 and hepatotoxicant acetaminophen. Mechanistic studies, which 4.3. Neutral Compounds 1371 established the cytochrome P450 (CYP) mediated oxidation of acetaminophen to a reactive quinoneÀimine intermediate,7 cap- 5.0. Structural Alert and RM Analyses for the Top 20 able of depleting levels of the endogenous antioxidant glutathione Drugs in the US Market in 2009, by Dispensed (GSH) and/or binding covalently to liver proteins leading to Prescriptions 1375 liver injury, have served as a paradigm for drug toxicity assessment 6.0. Structural Alert and RM Analyses for the Top 20 over the decades. Studies with model compounds and drugs such Drugs in the US Market in 2009, by Sales 1383 as acetaminophen have aided in defining the role that chemical 7.0. Structural Alert and RM Analyses for the Remaining stress and bioactivation can have in biological outcomes that may ff 180 Drugs in the US Market in 2009, by Dispensed be triggered by RMs. These include e ects on cell signaling/ defense, transcription factors, apoptosis, necrosis, and inflamma- Prescriptions 1385 tion, activation of the innate and adaptive immune systems. 8.0. Structural Alert and RM Analyses for the Remaining Under the basic premise that a RM-negative compound could 180 Drugs in the US Market in 2009, by Sales 1393 mitigate immune-mediated IADR risks, most drug discovery 9.0. Lessons Learned from the Structural Alert/RM efforts have implemented screens to assess RM formation from Analyses for Drugs Associated with IADRs and the new compounds with the ultimate goal of minimizing or eliminat- Top 200 Drugs of 2009 1395 ing this liability through iterative design. General avoidance of Associated Content 1399 functional groups that have been associated with RM formation “ ” 8 Author Information 1399 (referred to as structural alerts ) is almost a norm in drug design, particularly at the lead optimization/candidate selection Abbreviations 1399 stage. While these approaches appear reasonable in the quest for References 1399 safer medicines, there is a growing concern that the perceived safety hazards associated with incorporation of a structural alert may be over exaggerated. For instance, almost half of all new 1.0. INTRODUCTION small molecule drugs launched in the past five years possess at Despite tremendous strides in the field of chemical toxicology, least one structural alert. Moreover, the vast majority of drugs reliably predicting the occurrence of idiosyncratic adverse drug possess a phenyl ring, which is a structural alert in its own right, reactions (IADRs) for new drug candidates represents a significant since phenyl ring metabolism to the corresponding phenol can challenge. The term “idiosyncratic” simply represents terminol- proceed through a reactive epoxide intermediate. Aromatic ring epoxidation also represents the rate-limiting step in the carcino- ogy suggesting that little is known about the underlying mechan- ff ism and that the toxicity is unpredictable. Many IADRs possess genic and/or hepatotoxic e ects of organic solvents such as an immune component and occur in only a subset of patients benzene and bromobenzene. In addition, there are real concerns that simple RM screening tools,9 such as GSH trapping and either acutely or as a delayed response. The observations that covalent binding assays, may be too stringent and could halt the certain IADRs (e.g., hypersensitivity associated