Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist

Abstract

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.

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules

“…Previous reports have hypothesized a sigmoidal relationship between the log P value of drugs, and their cell membrane permeability [9]. Therefore, among of the more commonly employed prodrug strategies for improving the absorption of poorly permeable drugs is to increase the lipophilicity (log P) of drug [10]. Although, the use of log P to understand permeability is an over-simplification of the complex process, some correlation exists as majority of oral drugs fall between 1-5 log P values.…”

Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

“…The labile groups are usually broken by enzymatic action, and the parent drug is freed to produce its pharmacological action. The prodrug approach has been widely used in the development of bacampicillin, chloramphenicol, pivampicillin, and enalapril (Van Gelder et al 2000;van De Waterbeemd et al 2001;Beaumont et al 2003).…”

Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes

“…Usually this kind of tuneable dual reactivity is only achieved using the double prodrug strategy [33], but that involves formaldehyde liberation over which there toxicity concerns [34][35][36]. Additionally, these α-(acylamino)acyl derivatives display log P values that suggest they should be well absorbed by biological membranes.…”