What is an ester prodrug?

Many drugs are administered at sites that are remote from their site of action. The most common route of drug delivery is the oral route. The optimal physicochemical properties to allow high transcellular absorption following oral administration are well established and include a limit on molecular size, hydrogen bonding potential and adequate lipophilicity. For many drug targets, synthetic strategies can be devised to balance the physicochemical properties required for high transcellular absorption and the SAR for the drug target. However, there are drug targets where the SAR requires properties at odds with good membrane permeability. These include a requirement for significant polarity and groups that exhibit high hydrogen bonding potential such as carboxylic acids and alcohols. In such cases, prodrug strategies have been employed. The rationale behind the prodrug strategy is to introduce lipophilicity and mask hydrogen bonding groups of an active compound by the addition of another moiety, most commonly an ester. An ideal ester prodrug should exhibit the following properties: 1) Weak (or no) activity against any pharmacological target, 2) Chemical stability across a pH range, 3) High aqueous solubility, 4) Good transcellular absorption, 5) Resistance to hydrolysis during the absorption phase, 6) Rapid and quantitative breakdown to yield high circulating concentrations of the active component post absorption. This paper will review the literature around marketed prodrugs and determine the most appropriate prodrug characteristics. In addition, it will examine potential Discovery approaches to optimising prodrug delivery and recommend a strategy for prosecuting an oral prodrug approach.

Keywords: ester prodrugs, oral absorption, poorly permeable compounds, physicochemical properties, drug target

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Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), has often been implicated in prostate cancer. Studies in prostate tumor cell lines revealed that Akt activation is probably important for the progression of prostate cancer to an androgen-independent state. Investigations of human prostate cancer tissues show that although there is neither Akt gene amplification nor enhanced protein expression in prostate cancer compared to normal tissue, poorly differentiated tumors exhibit increased expression of a phosphorylated (activated) form of Akt compared to normal tissue, prostatic intraepithelial neoplasia (PIN) or well-differentiated prostate cancer. Akt phosphorylation is accompanied by the inactivation of ERK, a member of the mitogen activated protein kinase (MAPK) family. In this article, we postulate that Akt promotes androgen-independent survival of prostate tumor cells by modulating the expression and activation of the androgen receptor (AR).

Keywords: akt, pi3k, androgen receptor, mapk, pten, prostate cancer

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The cardiovascular effects of estrogen have recently become a focus of basic and clinical cardiovascular medicine because of the multiplicity of its beneficial effects. Various basic and clinical studies have revealed that estrogen has potent cardiovascular effects against ischemic or non-ischemic injury of the heart and vessels, leading to the concept that administration of estrogen may reduce cardiovascular disease in postmenopausal women. Indeed, among the groups of the postmenopausal women who have a higher risk of cardiovascular diseases, the hormone therapy has been associated with improved outcomes for cardiovascular events. Estrogen binds to the estrogen receptor, which is a member of the steroid hormone family of nuclear receptors and is the estrogen response element in target genes, leading to the transcriptional regulation of many genes. In addition to these genomic effects of estrogen, it has been recently reported that estrogen can have rapid “nongenomic” effects. In contrast to such data, recent clinical prevention trials in postmenopausal women treated with a combination of estrogen and progestins have not revealed any beneficial effects on cardiovascular morbidity or mortality, and estrogen itself increases the risk of endometrial and breast cancer. Under these circumstances, a selective estrogen receptor modulator (SERM), which exerts estrogenic agonistic or antagonistic actions on various tissues, has been recently introduced for new hormone therapy because it reduces the adverse effects of estrogen. Here, we summarize the effects of estrogen and SERM on the cardiovascular system and discuss cellular mechanisms that may be involved.

Keywords: cardiovascular disease, clinical trials, estrogen, hormone replacement therapy, selective estrogen receptor modulator

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Exposure to estrogens has been long associated with the genesis of human malignancies, including breast, ovarian, and endometrial cancer. A variety of phase I and II enzymes are involved in the metabolic activation and deactivation of estrogens, including cytochrome P450 isoforms, estrone sulfatase, sulfotransferases, catechol-o-methyltransferase, and uridine-5-diphosphate glucuronosyltransferase. In addition, at least one ATP-binding cassette gene (i.e., ABCG2) is involved in estrogen transport. Variability in the expression levels of these proteins may have important consequences for an individuals susceptibility to certain malignancies. Naturally occurring variants in the genes involved in estrogen exposure levels have been identified that might affect protein function and expression. This review focuses on recent advances in the pharmacogenetics of these proteins, and discusses potential clinical ramifications of these genetic variants.

Keywords: estrogen, metabolism, transport, cancer, pharmacogenetics

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Cytochrome P450 2B genes have been used extensively as prototypical models to study phenobarbital induction of P450 enzymes. Although its basal hepatic abundance is relatively low, CYP2B is highly inducible by various chemicals. Cross regulation and shared substrate specificity of CYP2B with CYP3A and other drug metabolizing enzymes lend support to the pharmacological and toxicological significance of CYP2B induction. The constitutive androstane receptor (CAR) appears to be one of the main regulators involved in transcriptional activation of CYP2B genes, although pregnane X receptor (PXR), glucocorticoids receptor (GR), and other nuclear receptors may be required for their optimal activation. In this article, we review current advances in the mechanisms of species-specific activation of CYP2B genes by CAR, with the human CYP2B6 gene being a main focus. Several recent findings, including discovery of a human CAR specific activator 6-(4-chlorophenyl:imidazo[2,1-b]thiazole-5carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), identification of a far-distal xenobiotic-responsive enhancer module (XREM) in the CYP2B6 gene promoter, and generation of CAR-null mice as a model of characterizing CAR target gene expression, will also be discussed. These findings should provide greater insight into the mechanisms and species-specific differences of CAR regulation of CYP2B and other target genes.

Keywords: cyp2b, nuclear receptor, car, pxr, liver, induction, regulation

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For the pharmaceutical industry, one of the challenges in evaluating the risk of future compound attrition at the discovery stage is the successful prediction of the major routes of clearance in humans. For compounds cleared by metabolism, such information will help to avoid the development of compounds that will exhibit large interpatient differences in pharmacokinetics via 1) routes of metabolism catalyzed by functionally polymorphic enzymes and / or 2) clinically significant metabolic drug-drug interactions, in the later stages of development. The degree of intersubject variability that is acceptable for a drug candidate is uncertain in the discovery stage where knowledge of other important factors is limited or unavailable (i.e. therapeutic index, pharmacodynamic variability, etc). Reaction phenotyping is the semi-quantitative in vitro estimation of the relative contributions of specific drug-metabolizing enzymes to the metabolism of a test compound. However, reaction phenotyping in the discovery stage of drug development is complicated by the absence of radiolabelled parent compound or metabolite bioanalytical standards relative to later stages of development. In this commentary, some of the approaches, based on published data, which can be taken to overcome these challenges are discussed. In addition, knowledge of the molecular structure (i.e. specific chemical substituents), physicochemical properties, and routes of clearance in animals can all help in making a successful prediction for the routes of clearance in humans. In combination, the objective of these studies should be to reduce to a minimum the risk of finding significant inter-patient differences in pharmacokinetics at a later stage in development due to significant metabolism by polymorphic enzymes or drug-drug interactions. Consequently, this data should be used to avoid costly late stage attrition.

Keywords: reaction phenotyping, drug discovery, drug metabolizing enzymes