Soft drugs for dermatological applications: recent trends

Aprile, Silvio; Serafini, M. Teresa; Pirali, Tracey

doi:10.1016/j.drudis.2019.08.007

Cited by 13 publications

(7 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the basis of the patient history and clinical signs, and the label of the cosmetic products used, CMEA has the potential to induce dermatitis (Mertens et al, 2016). Activation of TRPV1 channels has been shown to be involved in skin inflammation (Gouin et al, 2018), and inhibition of TRPV1 channels represents an attractive target for the treatment of skin inflammatory disease (Aprile et al, 2019). Thus, activation of TRPV1 channels by CMEA may explain the mechanism of CMEA‐induced dermatitis observed in the animal models (Lanigan & Andersen, 1999).…”

Section: Discussionmentioning

confidence: 99%

Surfactant cocamide monoethanolamide causes eye irritation by activating nociceptor TRPV1 channels

Zhao

Wang

et al. 2021

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose Cocamide monoethanolamide (CMEA) is commonly used as a surfactant‐foam booster in cosmetic formulations. Upon contact with the eye or other sensitive skin areas, CMEA elicits stinging and lasting irritation. We hypothesized a specific molecular interaction with TRPV1 channels by which CMEA caused eye irritation. Experimental Approach Eye irritancy was evaluated using eye‐wiping tests in rabbits and mice. Intracellular Ca2+ concentrations and action potentials were measured using Ca2+ imaging and current clamp respectively. Voltage clamp, site‐direct mutagenesis and molecular modelling were used to identify binding pockets for CMEA on TRPV1 channels. Key Results CMEA‐induced eye irritation is ameliorated by selective ablation of TRPV1 channels.Rodents exhibit much stronger responses to CMEA than rabbits. In trigeminal ganglion neurons, CMEA induced Ca2+ influx and neuronal excitability, effects mitigated by a TRPV1 channel inhibition and absent in TRPV1 knockout neurons. In HEK‐293 cells expressing TRPV1 channels, CMEA increased whole‐cell currents by increasing channel open probability (EC50 = 10.2 μM), without affecting TRPV2, TRPV3, TRPV4, and TRPA1 channel activities. Lauric acid monoethanolamide (LAMEA), the most abundant constituent of CMEA, was the most efficacious and potent TRPV1 channel activator, binding to the capsaicin‐binding pocket of the channel. The T550I mutants of rabbit and human TRPV1 channels exhibit much lower sensitivity to LAMEA. Conclusions and Implication CMEA directly activates TRPV1 channels to produce eye irritation. Rabbits, the standard animal used for eye irritancy tests are poor models for evaluating human eye irritants structurally related to CMEA. Our study identifies potential alternatives to CMEA as non‐irritating surfactants.

show abstract

Section: Discussionmentioning

confidence: 99%

Surfactant cocamide monoethanolamide causes eye irritation by activating nociceptor TRPV1 channels

Zhao

Wang

et al. 2021

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…This allows the drug to act primarily in the dysfunctional region restricting migration to neighboring tissues as it will be metabolized outside the target tissue. These drugs are usually administered topically or locally (e.g., eyes, skin, nasal mucosa, bone articulations, lungs, or gastrointestinal track) and are rapidly inactivated upon leaving the site of action, virtually eliminating their systemic exposure and thus increasing their safety (Aprile et al, 2019). Accordingly, considering the pharmacological and therapeutic properties of capsaicin, vanilloid-based soft drugs could contribute to the development of safer and more effective TRPV1 modulators.…”

Section: Trpv1 Soft Modulatorsmentioning

confidence: 99%

TRPV1 in chronic pruritus and pain: Soft modulation as a therapeutic strategy

Fernández-Carvajal

Fernández‐Ballester

Ferrer‐Montiel

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Chronic pain and pruritus are highly disabling pathologies that still lack appropriate therapeutic intervention. At cellular level the transduction and transmission of pain and pruritogenic signals are closely intertwined, negatively modulating each other. The molecular and cellular pathways involved are multifactorial and complex, including peripheral and central components. Peripherally, pain and itch are produced by subpopulations of specialized nociceptors that recognize and transduce algesic and pruritogenic signals. Although still under intense investigation, cumulative evidence is pointing to the thermosensory channel TRPV1 as a hub for a large number of pro-algesic and itchy agents. TRPV1 appears metabolically coupled to most neural receptors that recognize algesic and pruritic molecules. Thus, targeting TRPV1 function appears as a valuable and reasonable therapeutic strategy. In support of this tenet, capsaicin, a desensitizing TRPV1 agonist, has been shown to exhibit clinically relevant analgesic, anti-inflammatory, and anti-pruritic activities. However, potent TRPV1 antagonists have been questioned due to an hyperthermic secondary effect that prevented their clinical development. Thus, softer strategies directed to modulate peripheral TRPV1 function appear warranted to alleviate chronic pain and itch. In this regard, soft, deactivatable TRPV1 antagonists for topical or local application appear as an innovative approach for improving the distressing painful and itchy symptoms of patients suffering chronic pain or pruritus. Here, we review the data on these compounds and propose that this strategy could be used to target other peripheral therapeutic targets.

show abstract

“…UPLC−MS (ESI+) m/z 308.14 (MH + ). (10). The title compound was prepared following the same procedure as the one outlined for 6, the only difference being that (3-acetylphenyl)boronic acid was replaced by (4propanoylphenyl)boronic acid.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Previously we described the discovery of 1 (see Figure ), a “soft” PDE4 inhibitor designed to achieve high local skin concentrations but low systemic exposure upon topical application due to a high hepatic clearance. , The compound was proven to be efficacious in AD patients, but nevertheless, the clinical development of 1 was discontinued in part due to safety concerns related to the systemic exposure of metabolites of the candidate drug. In most patients 1 was rapidly converted to inactive metabolites as predicted, but unfortunately in some individuals a different metabolic pathway was observed resulting in high levels of an active pyridine N -oxide metabolite.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel “Dual-Soft” PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis

et al. 2020

View full text Add to dashboard Cite

We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.

show abstract

Soft drugs for dermatological applications: recent trends

Cited by 13 publications

References 79 publications

Surfactant cocamide monoethanolamide causes eye irritation by activating nociceptor TRPV1 channels

Surfactant cocamide monoethanolamide causes eye irritation by activating nociceptor TRPV1 channels

TRPV1 in chronic pruritus and pain: Soft modulation as a therapeutic strategy

Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel “Dual-Soft” PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis

Contact Info

Product

Resources

About