Identification and evaluation of molecular properties related to preclinical optimization and clinical fate.
ABSTRACT The economic case for fundamental changes that are required to ensure long term viability of the pharmaceutical industry demands a close look at which compounds are advanced into clinical development. This perspective will cover recent efforts that have had the greatest influence on defining the optimal range of physical properties of compounds that are intended to act as human therapeutic agents. Our focus will be on models and properties that are most amenable to change via synthetic design, are potentially fixable in the lead optimization process, and have the greatest impact on overall attrition in clinical development. In particular, we will examine the optimal physicochemical properties for oral absorption based on solubility, permeability, and a few easily computed parameters. Additionally, the fate of compounds that have entered clinical trials provides a compelling case for adhering to the defined properties ranges. Finally, emerging data suggests that there has been a shift in the leading causes of compound attrition, and attention should now be focused on building toxicological models to guide drug discovery efforts.
- Medicinal Chemistry Communication 01/2011; 2(2):91. · 2.63 Impact Factor
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ABSTRACT: Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.European Journal of Medicinal Chemistry 09/2014; 84:284–301. · 3.43 Impact Factor
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ABSTRACT: The development of new drugs today is a hugely expensive process, with estimated costs of up to $1 billion to take a drug through to market. However, despite this seemingly massive expenditure, statistics show that the great majority of prescription drugs on the mar- ket today are only effective for around 40 % of the patients to whom they are administered. Worse still, recently there have been a series of high-profile instances where potentially block-busting FDA-approved drugs have subsequently been withdrawn due to unanticipated side effects that were only revealed when the drug entered use in the general population. A variety of factors are at play in underpinning such statistics, but at the heart of the problem is the fact that, despite the extensive knowledge being generated in the postgenomic era about the genetic differences between individuals, Western medicine still today largely ignores such differences. The hope therefore is that by gaining a greater understanding of the indi- vidual nature of disease progression and of drug response, we might move toward a new era of personalized medicine in which the right drug is prescribed at the right dose to treat the precise disease afflicting the specific patient. As a step along this road, this review will dis- cuss new approaches in the pharmacogenomics field to understanding in a quantitative man- ner the molecular consequence of polymorphic variation and mutation, both on encoded pro- tein function and on protein-drug interactions.Pure and Applied Chemistry 01/2008; 80(8):1811-1820. · 3.11 Impact Factor