Identification and evaluation of molecular properties related to preclinical optimization and clinical fate.

Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
Medicinal Chemistry (Impact Factor: 1.39). 12/2005; 1(6):649-55. DOI: 10.2174/157340605774598081
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Using databases of oral drugs and recent compounds from the patents of major pharmaceutical companies, trends in molecular properties over time are identified. It is shown that the physical property profiles of oral drugs are not absolute, but depend on both ion class and the time of the drug invention. Properties examined include lipophilicity, molecular weight, hydrogen bond donors and acceptors, polar surface area, aromaticity, chirality and tetrahedral (sp3) carbon atom count. Lipophilicity is increasing over time in oral drugs that are neutral or acidic, but not in basic drugs, and has been converging in all ion classes towards a common constant range since the 1960s. In contrast, molecular weight is increasing over time in all ion classes. Hydrogen bond donors (OH + NH group count) are stable over time but hydrogen bond acceptors (O + N atom count) are increasing over time. It is shown that measures using sp3 atom and aromatic atom counts are inversely related and a new parameter, Ar atom count - sp3 atom count (Ar-sp3), describing shape or aromatic/aliphatic balance, is introduced. Ar-sp3 is constant over time in oral drugs, but is higher in patented compounds, independently of molecular weight and lipophilicity. The ion classes in patent compounds occupy distinct molecular weight/lipophilicity/shape chemical space. These properties are significantly increased versus oral drugs, with the exception of the most recently discovered acidic drugs, and occur in most, but not all target classes. While ceilings for lipophilicity in acids and neutral compounds may not have been reached, the design of potential drug molecules with reduced ADMET risk is indicated by a seeking a better balance between lipophilicity, 3-dimensionality and aromaticity.
    Medicinal Chemistry Communication 02/2011; 2(2):91. DOI:10.1039/c0md00157k · 2.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 08/2008; 80(8):1811-1820. DOI:10.1351/pac200880081811 · 3.11 Impact Factor
  • [Show abstract] [Hide abstract]
    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. DOI:10.1016/j.ejmech.2014.06.078 · 3.43 Impact Factor