As part of lead optimisation programs, much consideration has been directed towards the design and development of "more water soluble and readily developable" drug candidates. The advantages of such a strategy are clear as it will often enhance the speed of development and the success of the discovery program. However, in some cases, the biology and chemical characteristics of putative targets/receptors are such that the intrinsic potency of compounds can become rapidly diminished as the hydrophobicity (and possibly lipophilicity) of the compounds is decreased. This realisation, coupled with the understanding that a major limitation in the design of lipid-based formulations is the insufficient lipid solubility of a drug thereby limiting the unit dose that can be achieved, raises the following interesting possibility: that as part of a lead optimisation, it is worthwhile to at least explore more lipophilic (not hydrophobic) candidates as they may confer better potency while making them more amenable to formulation in a lipid-based formulation.
Fig 2 is a simple representation of this concept whereby the exploration of more hydrophilic and more lipophilic derivatives is considered while optimising the chemical scaffold and/or lead candidates. When exploring the more lipophilic candidates, the advantages include (i) a more complete exploration of the SAR of relevant scaffolds, (ii) possibly enhanced potency through increased lipophilicity, with a likely formulation approach being a lipid-based system to provide enhanced and reproducible bioavailability, and (iii) better protection of the overall intellectual property base surrounding the discovery program. The negative possibilities of exploring more lipophilic candidates include (i) the potential for increased drug metabolism due to increased lipophilicity of the compounds
(although this can be assessed in vitro), (ii) the increased reliance on a lipid-based formulation during pre-clinical and possibly clinical development, (iii) the possibility that oral bioavailability then becomes formulation-dependent due to the role of the lipid-based formulations, and (iv) an overall increase in the complexity (perceived or otherwise) of the development program.
Therefore, in situations where exploration of hydrophilic functional groups on a lead scaffold has led to a loss of potency or selectivity, consideration of the advantages of enhanced lipophilicity in the context of a more traditional lead optimisation may offer a means of addressing otherwise intractable developmental issues with the particular target SAR profile.
Figure 2. Representation of the changing effects of altering the lipophilicity characteristics of a compound series on its "developability profile" (ignoring the impact on metabolism and toxicology issues). For the purposes of the diagram, it is simplistically assumed that aqueous and lipid solubility are reasonable surrogates for the unit dose that could be formulated in a conventional oral solid dose form or a lipid-based formulation, respectively. The hatched box signifies the difficulties often encountered when formulating poorly water soluble/poorly lipid soluble drugs that have intermediate log P values.
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