DISCOVERY OF IMIQUIMOD

Discovery of Imiquimod

Discovery of Imiquimod

Introduction

Imiquimod, licensed as Aldara cream, serves as a good example of the serendipity and complexity involved in nonidealized drug discovery and development. Despite a long history in the development phase, imiquimod is now successful as an immunopotentiatory drug, although licensed only for a single indication (ano-genital warts). Imiquimod also has additional value in illustrating how research on an established drug can tell us a good deal about how to apply the new technologies to discovering the next generation of immunopotentiatory drugs. (Masihi 2000, 56-78) From this brief account of the generic new technologies of drug discovery, it is apparent that many of the approaches are not directly relevant to the discovery of immunopotentiatory drugs.

Instead they are biased towards disease-specific targets which may not be helpful in identifying immunopotentiatory targets (except the genes responsible for primary immunodeficiencies of which more than 30 are already known. Despite this, the power and scale of generic NCE screening is likely to prove useful for immunomodulation as more and more receptor families are characterized and intracellular pathways expanded through identification of key molecules in signalling cascades, many of which will be essential to immune function. The nature of targets that might prove valuable in the discovery of immunopotentiatory NCEs is considered later. (Masihi, 2000, 56-78)

It takes around 10 years to take a drug from preclinical safety testing to licensure as a medicine, and the period from initial discovery of a biological activity to preclinical development is also several years. This means that the compounds we have today as candidates for broadly applicable immunopotentiatory drugs were first identified long before the revolution in drug discovery technology.

Imiquimod was first noted in a programme screening for antiherpes virus activity in the 1980s. The slight toxicity of the drug series produced a slight reduction in herpes cytopathology in Vero cell cultures sufficient for compounds to be tested further in a guinea-pig model. Here, complete protection against herpetic lesions was observed. In fact all the antiviral effects of imiquimod were subsequently shown to be a consequence of its ability to induce pro-inflammatory cytokines driving Th1 immune responses. Although a small molecule, imiquimod has limited oral bioavailability and is effectively restricted to topical application. (Masihi 2000, 56-78)

Explanation

Target identification

In vitro analyses of imiquimod's effects on immune cells show that it induces the synthesis of IFN-a, TNF-a and other pro-inflammatory cytokines. It also induces antigen nonspecific B-cell proliferation through a mechanism that may be unrelated to cytokine induction. In vitro effects seem to depend on the activation of transcription factors such as NF?B that bind to promoter regions of IFN-a and other cytokines including IL-1, IL-1RA, IL-6, IL-8 and IL-12p40, although IFN-a seems to be induced at lower concentrations of drug. In vivo studies of topical application in hairless mice have shown that imiquimod induces increased IFN-a mRNA and increased IFN-a and TNF-a proteins in treated skin. These effects occur within 1-4 h. Accompanying changes include enlargement, morphological activation and increased migration of Langerhans ...