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

• Published in: European journal of pharmacology 2024-01, Vol.962, p.176202-176202, Article 176202
• Main Authors: Kubota-Ishida, Natsuki, Kaji, Chizuko, Matsumoto, Shogo, Wakabayashi, Tsubasa, Matsuhira, Takashi, Okura, Iori, Cho, Naoki, Isshiki, Satoshi, Kumura, Ko, Tabata, Yuji
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Cyclic Nucleotide Phosphodiesterases, Type 4; Cytokines; Dermatitis, Atopic - drug therapy; Ferrets; Humans; Inflammation - drug therapy; Leukocytes, Mononuclear; Mice; Phosphodiesterase 4 Inhibitors - pharmacology; Phosphodiesterase 4 Inhibitors - therapeutic use; Psoriasis - pathology; Rats
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.176202

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.