ME3183, a novel phosphodiesterase-4 inhibitor, exhibits potent anti-inflammatory effects and is well tolerated in a non-clinical study.

Phosphodiesterase 4 (PDE4) inhibitors are expected to exhibit efficacy against inflammatory diseases due to their broad pharmacological activity. The launched PDE4 inhibitors apremilast, crisaborole, and roflumilast have not exhibited sufficient inhibitory potential due to poor margins of effectiveness and tolerability. In this report, we describe the non-clinical efficacy, brain translocation, and vomit-inducing effects of ME3183 compared with apremilast. ME3183 showed extensive cytokine suppression in vitro studies using human peripheral blood mononuclear cells and T cells. ME3183 also significantly suppressed skin inflammation in a chronic oxazolone-induced dermatitis model and showed antipruritic effects in a substance P-induced mouse pruritus model. In these in vitro and in vivo studies, ME3183 also significantly suppressed cytokines, and focusing on tumor necrosis factor-α as a psoriasis-related cytokine and interleukin-4 as an atopic dermatitis-related cytokine, ME3183 potently inhibited both cytokines. ME3183 showed in vivo efficacy at lower doses than apremilast. The brain distribution of ME3183 was sufficiently low in mice and rats. The effective dose of ME3183 for emesis was similar to that of apremilast in ferrets. Given its high-potency inhibitory effects, ME3183 would have a wide margin of efficacy and tolerability. These wide margins demonstrate the effectiveness of ME3183 in treating many inflammatory diseases, such as psoriasis and atopic dermatitis. An on-going phase 2 trial is expected to further demonstrate the efficacy and safety of ME3183.

Anti-inflammatory effects of a novel phosphodiesterase-4 inhibitor, AA6216, in mouse dermatitis models.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is commonly treated with corticosteroids. However, these drugs have long-term adverse effects, representing an unmet need for new treatments. AD is associated with dysregulation of phosphodiesterase 4 (PDE4) activity in inflammatory cells and the topical PDE4 inhibitor, crisaborole, is approved by the US FDA for mild-to-moderate AD. In this study, we compared the effects of a novel PDE4 inhibitor, AA6216, with those of crisaborole on skin inflammation. We found that AA6216 is a more potent inhibitor of PDE4 and of cytokine production (TNF-α, IL-12/23p40, IL-4, IL-13, and IFN-γ) by human peripheral blood mononuclear cells (PBMCs) stimulated by phytohemagglutinin (PHA) or anti-CD3 antibodies, with IC50 values ranging from 5.9 to 47 nM. AA6216 also significantly suppressed skin inflammation in three mouse models of dermatitis. In acute and chronic oxazolone-induced dermatitis models, topical AA6216 exhibited stronger inhibitory effects on ear inflammation and cytokine production (TNFα, IL-1ß, and IL-4) in skin lesions compared with crisaborole. In a Dermatophagoides farinae-induced dermatitis model, AA6216 significantly reduced the dermatitis score, based on the development of erythema/hemorrhage, scarring/dryness, edema, and excoriation/erosion, compared with a clinically used topical AD drug, tacrolimus. These results suggest the possibility that AA6216 is a novel and effective topical therapeutic agent for the treatment of dermatitis including AD.

A novel phosphodiesterase 4 inhibitor, AA6216, reduces macrophage activity and fibrosis in the lung.

Idiopathic pulmonary fibrosis (IPF) is an intractable disease with poor prognosis, and therapeutic options are limited. While the pathogenic mechanism is unknown, cytokines, such as transforming growth factor (TGF)-ß, and immune cells, such as monocytes and macrophages, that produce them, seem to be involved in fibrosis. Some phosphodiesterase 4 (PDE4) inhibitors reportedly have anti-fibrotic potential by acting on these disease-related factors. Therefore, we evaluated the effect of a novel PDE4 inhibitor, AA6216, on nonclinical IPF-related models and samples from IPF patients. First, we examined the inhibitory effect of AA6216 on the production of TGF-ß1 from a human monocytic cell line, THP-1. Second, we analyzed the impact of AA6216 on TNF-α production by human alveolar macrophages collected from patients with IPF. Finally, we investigated the anti-fibrotic potency of AA6216 on bleomycin-induced lung fibrosis in mice. We found that AA6216 significantly inhibited TGF-ß1 production by THP-1 cells. It also significantly suppressed TNF-α production by alveolar macrophages from patients with IPF. In the mouse model of bleomycin-induced pulmonary fibrosis, therapeutic administration of AA6216 significantly reduced fibrosis scores, collagen-stained areas, and TGF-ß1 in bronchoalveolar lavage fluid. AA6216 may represent a new agent for the treatment of IPF with a distinct mechanism of action from that of conventional anti-fibrotic agents.

Evaluation of four antiseptics using a novel murine norovirus.

We isolated a novel murine norovirus (MNV), MT30-2 strain, from feces of conventional mice in Japan to evaluate the virucidal activity of four antiseptics. The MNV MT30-2 strain was inactivated by as little as 0.2% (w/v) povidone-iodine (PVP-I) and 0.1% (w/v) sodium hypochlorite (NaOCl) treatment as determined by a novel plaque assay. Importantly, PVP-I reduced the MNV titer by 4 log(10) within 15 s of exposure. The other two antiseptics, benzethonium chloride (BEC) and chlorhexidine gluconate (CHG), did not reduce the MNV titer even when treatment lasted for 60 s. When the virus titer was reduced by PVP-I or NaOCl treatment, the amount of MNV RNA was not reduced, indicating that the presence of viral RNA was not related to the virucidal activity of the antiseptics. PVP-I and NaOCl will be useful in controlling the spread of MNV, which is a common problem in mice colonies. In this study, we isolated a novel MNV and newly revealed that two antiseptics (PVP-I and NaOCl) were able to inactivate MNV at low concentrations and in a short contact time.