Current Pharmaceutical Design - Volume 15, Issue 19, 2009

Efficacy in preclinical models alone is insufficient for advancing compounds to drug development. This fact has led to the incorporation of drug metabolism and pharmacokinetics (DMPK) as one of the key components along with medicinal chemistry and biology during the lead optimization and characterization processes. Exploratory DMPK plays a key role in the drug discovery paradigm by assisting in selecting and designing therapeutic drug candidates with strong potency and favorable human pharmacokinetic properties. This special issue of Current Pharmaceutical Design focuses on the fundamentals and the applications of DMPK in early drug discovery research and acknowledges the efforts from contributors in making this issue possible. Tang W. and Lu AYH. [1] at the Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories and the Department of Chemical Biology, Rutgers University, respectively, outline a brief overview on several DMPK strategies employed during the lead optimization processes. The authors describe several case studies and provide future directions of overcoming deficiencies in the current practice by developing tools enabling better prediction of clinical outcomes. Di L, Kerns EH and Carter GT. [2] from the Department of Chemical Technologies, Wyeth Research, introduce the concept of drug-like properties as an integrated part of the drug discovery process which is able to offer an early alert to potential issues, to guide structural modification, to prioritize chemical series and to diagnose in vivo PK and pharmacology.

Pharmacokinetics has been recognized as one of the elements determining the probability of success in pharmaceutical research. As a result, compounds are routinely evaluated in drug discovery for their absorption, distribution, metabolism and elimination properties. The primary objective of these studies is to eliminate “flawed” molecules or a structural class based on preset selection criteria, while building a knowledge base for compilation of structure-activity relationships to guide chemistry synthesis efforts. This article is intended to provide a brief overview combined with critical evaluation on several strategies employed during lead optimization processes, and the analyses are supported by case studies. Future directions are discussed in the context of overcoming deficiencies in the current practice by developing tools enabling better prediction of clinical outcomes.

The pharmaceutical industry is facing an ever increasing challenge to deliver safer and more effective medicines. Traditionally, drug discovery programs were driven solely by potency, regardless of the properties. As a result, the development of non-drug-like molecules was costly, had high risk and low success rate. To meet the challenges, the bar has been rising higher for drug candidates. They not only need to be active, but also drug-like to be advanced to clinical development. Drug-like properties, such as solubility, permeability, metabolic stability and transporter effects are of critical importance for the success of drug candidates. They affect oral bioavailability, metabolism, clearance, toxicity, as well as in vitro pharmacology. Insoluble and impermeable compounds can result in erroneous biological data and unreliable SAR in enzyme and cell-based assays. Rapid metabolism by enzymes and high efflux by transporters can lead to high clearance, short half-life, low systemic exposure and inadequate efficacy. Early property information helps teams make informed decisions and avoids wasting precious resources. Structure-property relationships are essential to guide structural modification to improve properties. High throughput ADME/TOX assays have been implemented and are being widely used to drive drug discovery projects in parallel with activity screening. Property design has become an integrated and inseparable part of the modern drug discovery paradigm. The approach has been proven to be a winning strategy.

The high attrition rate in drug development and the deteriorated drug ability as a result of the shifted chemical space of new therapeutic target for unmet medical needs have posed drastic challenges in current drug discovery. It has triggered the strategic transition in the past decade into parallel assessment of efficacy and comprehensive ADMET (absorption, distribution, metabolism, elimination and toxicity) properties of new chemical entities (NCEs) in the lead selection and optimization stages, to convert chemically a problematic NCE to an “all-around” candidate. This review summarizes multiple in silico, in vitro and in vivo ADMET filters developed and implemented in various stages of drug discovery to flag potential ADMET issues in the clinic. The full awareness of the benefits and limitations of each tool assures right questions to be answered using right tools at right time. The integrated ADMET risk assessment will allow project teams to have a clear vision in terms of the competitive position of own NCEs against comparable marketed drugs.

Drug metabolism and pharmacokinetics (DMPK) represents a critical component in support of drug discovery and development. This is because the therapeutic efficacy of a drug is dependent on its exposure which in turn is dictated in part by metabolic stability of the molecule. In addition, drug metabolism may lead to the formation of metabolites that can either be pharmacologically active or elicit adverse effect. On this basis, metabolite identification and profiling have become a routine exercise during lead optimization and subsequent development processes. The current communication provides an overview on the account of metabolite identification and profiling in support of drug design with an additional emphasis on the commonly used analytical techniques. The discussion is supported by case studies. Future directions are discussed in the context of newer platforms of technology and bioanalytical approaches enabling better operation efficiency in pharmaceutical research.

Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to the parent active drug inside the body. Prodrugs can enhance the therapeutic efficacy and/or reduce adverse effects via different mechanisms, including increased solubility, improved permeability and bioavailability, prolonged half-life, and tissue-targeted delivery. Besides the prodrug itself, optimization of vehicles and other enhancement techniques is important as well. Strategies to improve the oral bioavailability and achieve tumor-specific targeting have been the most important developments in prodrug design during the last 5 years. This review describes recent developments in orally administered and tumor-targeted prodrugs. Pharmacokinetic and pharmacodynamic evaluations of these prodrugs are systematically introduced in this review.

The advances in high-speed synthesis technologies have produced a large number of biologically active new chemical entities (NCEs) for developability assessment. Current drug discovery efforts have been focused on identifying drug metabolism and pharmacokinetic (DMPK) issues at the earliest possible stage in order to reduce the attrition rate of drug candidates during the development phase. Mass spectrometry (MS) has proven a powerful tool in providing rapid qualitative and quantitative measurements of drug molecules for DMPK studies in both drug discovery and development. Although mass spectrometers can serve as separation devices, for most pharmaceutical applications, some form of chromatography is combined with MS. For most MS-based methods, tandem mass spectrometry (MS/MS) utilizes atmospheric pressure ionization (API) and chromatographic techniques. This review describes the major hyphenated chromatography- mass spectrometry techniques and their applications in supporting exploratory DMPK studies including various in vitro and in vivo PK and metabolite identification profiles.

The rising costs and time associated with bringing new medicines to the market have created a need for a new paradigm for reducing the attrition rates of drug candidates in both preclinical and clinical development stages. Early appraisal of drug metabolism and pharmacokinetic (DMPK) parameters is now possible due to several higher throughput in vitro and in vivo screens. This knowledge of DMPK properties should not only shorten the timelines for the selection of drug candidates but also enhance the probability of their success for development. The role of DMPK researchers in the drug research paradigm should not be limited to screening a large array of compounds during the lead optimization process but should include a strive for an understanding of the absorption, distribution, metabolism, excretion, and potential drug-related toxicities of a chemical series. As an example, in this article we present a specific DMPK research screening paradigm and describe a case study using the Thrombin Receptor Antagonist program. This screening paradigm followed by the extensive lead optimization process culminated in the selection of SCH 530348, a potent, selective and orally active thrombin receptor antagonist for the treatment of thrombosis.