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COVALENT BINDING IN DRUG DISCOVERY AND DEVELOPMENT. A PRAGMATIC VIEW OF THE ISSUE OF REACTIVE INTERMEDIATES.

Thomas A. Baillie, Department of Drug Metabolism, Merck Research Laboratories,

WP75A-303, West Point, PA 19486, U.S.A.

The generation of reactive, electrophilic metabolites from drug candidates is of concern within the pharmaceutical industry in light of the persuasive body of evidence which has accrued over the past 30 years implicating a role for such species as mediators of a diverse array of drug-induced toxicities. While the formation of "hard" electrophiles (e.g. carbonium, nitrenium ions), which preferentially alkylate nucleic acids and may initiate genotoxic lesions, is rather rare in contemporary drug discovery programs, "soft" electrophiles, which bind selectively to peptides (e.g. glutathione) and proteins, are generated during the metabolism of a broad range of functional groups, and therefore are relatively common.

With recent advances in the sensitivity and versatility of analytical techniques (notably those based upon mass spectrometry), and the wider use of radiolabeled compounds early in the drug discovery process, it has become easier to detect, identify and quantify the covalent adducts to peptides and (in favorable cases) proteins, to which reactive intermediates give rise. Similarly, methods to study end-products of reactive oxygen species have become relatively sophisticated, such that protein and lipid damage mediated by free radical processes also can be detected and quantified. Unfortunately, these advances in analytical methodologies have far outstripped our understanding of the biological processes which underlie the toxic effects of reactive intermediates, such that it becomes very difficult to evaluate the significance of reactive metabolite formation in the context of drug safety. In this regard, many important questions raised during the course of drug discovery cannot be answered based on our limited understanding of toxicology at the molecular level, e.g. What level (if any) of covalent binding to liver proteins might be "acceptable" in a drug candidate taken into development? What protein targets are critical to the viablity of the cell, and which of these are likely to be adducted by specific reactive intermediates? Might there be a dose threshold for toxicity of a given reactive intermediate, and what are the factors which determine this value? How can we forecast the risk of idiosyncratic toxicity mediated by the human immune system when presented with potentially immunogenic drug-protein conjugates?

In light of the many uncertainties associated with exposure to biological reactive metabolites, it seems prudent in the drug discovery process to attempt to minimize the risk of encountering adverse reactions in preclinical and clinical safety evaluation by selecting candidates that have a low propensity to undergo metabolic activation. This objective, in turn, requires some appreciation of the mechanisms by which certain functional groups in a new chemical entity may be metabolized to reactive electrophiles, so that appropriate chemical modifications can be made to the lead structures. In this presentation, examples will be given of strategies that have been employed by Drug Metabolism and Medicinal Chemistry at Merck to minimize the risk of taking into development compounds that are "flawed" with respect to their ability to generate chemically reactive intermediates.

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A COCKTAIL HOUR (Cash Bar) will begin at 5:30, followed by dinner at 6:30 PM. The cost of the DINNER is $45, including tax and gratuities. The cost of the DINNER for University Faculty and Students is $20. Checks or cash only. Credit cards cannot be accepted. Entree choices are Prime Rib of Beef, Baked Filet of Flounder, or Pasta Primavera. RESERVATIONS for the dinner must be made with your choice of entree by November 3 and may be made in several ways:

1. with your committee person
2. calling or faxing Emily Young at (610) 326-9568
3. on our website at www.dvdmdg.org or
4. by mail to Emily Young, 228 Maugers Mill Rd., Pottstown, PA 19464

(e-mail addresses of the steering committee members can also be found at the site)

Cancellations cannot be honored after November 5.

 

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