Description
Aldara was launched in the US for the topical treatment of genital warts
caused by human papillomavirus (HPV). It can be prepared in a six step approach
beginning with the nucleophilic substitution of 4-chloro-3-nitroquinolone with
isobutylamine or via a thermal electrocyclic ring closure of 1 - and 2-azahexatriene
systems. Aldara has antiviral and antitumor properties, with the former activity arising
from the induction of cytokines, in particular, INF-α. Aldara also induces TNF-γ, IL-1α, IL-1β, IL-1ra, IL-6, IL-8, IL-10, GM-CSF, G-CSF and MID-la formation 1-4 hr after
stimuli. The exact cells responsible for the response have not been determined,
however, it is not activating T lymphocytes, NK cells, B lymphocytes, or dendritic stem
cells but monocytes (CD14+, CD36+, HLA-DR+, HLA-DQ±, CD19-, CD16- and CD23-) are
partly responsible. The speculation is that Aldara may interact with a kinase
modulating the transduction pathway leading to cytokine genes. There is no direct
antiviral activity (induction of IFN does not follow true dose response) and it is not mutagenic. The hydroxylated metabolite also induces IFN-α.
Chemical Properties
White to off white crystalline powder
Originator
3M Pharmaceuticals (US)
Definition
ChEBI: Imiquimod is an imidazoquinoline fused [4,5-c] carrying isobutyl and amino substituents at N-1 and C-4 respectively. A prescription medication, it acts as an immune response modifier and is used to treat genital warts, superficial basal cell carcinoma, and actinic keratosis. It has a role as an antineoplastic agent and an interferon inducer.
Indications
Imiquimod (Aldara) is a topical immune response modifier
approved for the treatment of anogenital warts
(condylomata acuminata). The exact mechanism of action
is unknown; it has no direct antiviral activity in
vitro. It is thought to work in vivo by inducing the production
of tumor necrosis factor (TNF α ), interferons
(IFN)α and γ , and other cytokines with antiviral activity.
It may also be useful for treatment of other types of
warts, molluscum contagiosum, and certain forms of
skin cancer. Local irritant reactions related to the frequency
of application are common.
Brand name
Aldara (3M Pharmaceuticals).
Pharmaceutical Applications
An imidazoquinoline used for the treatment of genital and
perianal warts. While the mechanism of action is not precisely
known, it is thought to induce interferon. It has no direct antiviral
activity. The 5% cream applied three times a week for
up to 16 weeks resulted in total wart clearance in 50% of
patients, with a better response in women than in men. Local
reactions are common and include erythema, erosion, excoriation
and edema.
Biological Activity
Immunomodulator that displays antiviral and antitumor activity. Acts as a Toll-like receptor 7 (TLR-7) agonist; stimulates proinflammatory cytokine production and activates NF- κ B.
Biochem/physiol Actions
Imiquimod is a caspase 3 activator, which directly induces procaspase 3 cleavage to active caspase 3. Imiquimod induces apoptosis in vivo in basal cell carcinoma. Its anti-tumor activity is related to the induction of apoptosis. Imiquimod has anti-angiogenic, anti-inflammatory, anti-viral activities. Imiquimod also acts as an immune response modulator inducing the secretion of various cytokines and chemokines.
Veterinary Drugs and Treatments
An immune response modifier, imiquimod may be useful in the treatment of a variety of topical conditions in animals. It is labeled for use
on humans as a treatment for genital or perianal warts, superficial basal cell carcinomas and actinic keratoses of the face and scalp. In dogs
and cats, imiquimod potentially may be of benefit in treating feline herpes virus dermatitis, actinic keratosis, squamous cell carcinoma
and Bowen’s disease, papillomas virus lesions, and localized solar dermatitis or solar carcinoma in situ. In horses, imiquimod has been
anecdotally used with success in treating sarcoids.
Imiquimod stimulates the patient’s own immune system to release a variety of cytokines including interferon-alpha and interleukin-
12. Imiquimod itself does not have in vitro activity against wart viruses, but stimulates monocytes and macrophages to release cytokines
that induce a regression in viral protein production.
References
1) Hemmi?et al.?(2002),?Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway;?Nat. Immunol.?3?196
2) Stanley?et al.?(2002),?Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential;?Clin. Exp. Dermatol.?27?571
3) Schoen?et al.?(2006),?The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion;?J.Invest.Dermatol.?126?1338
4) Kan?et al.?(2012),?Imiquimod Suppresses Propagation of Herpes Simplex Virus 1 by Upregulation of Cystatin A via the Adenosine Receptor A1?Pathway.; J. Virol.?86?10338
5) Urosevic?et al.?(2004),?Imiquimod Treatment Induces Expression of Opioid Growth Factor Receptor; Clin. Cancer Res.?10?4959
6) Zagon?et al.?(2008),?Imiquimod Upregulates the Opioid Growth Factor Receptor to Inhibit Cell Proliferation Independent of Immune Function.; Exp. Biol. Med.(Maywood)?233?968
