ART26.12

ART26.12 (CAS No. 2766800-24-0) is a highly selective inhibitor of fatty acid binding protein 5 (FABP5) with a Ki of 0.77 ± 0.08 μM. It exhibits low cross-reactivity toward other FABP isoforms, including FABP3 (Ki = 71.32 ± 2.40 μM), FABP4 (Ki > 100 μM), and FABP7 (Ki = 18.99 ± 1.81 μM). ART26.12 shows high oral bioavailability in rats (73% at 10 mg/kg and 163% at 300 mg/kg) and demonstrates a no-observed-adverse-effect level (NOAEL) of up to 1000 mg/kg/day in both rats and dogs, indicating a favorable safety profile.

Pharmacologically, ART26.12 displays broad bioactivity across multiple neuropathic and inflammatory models. In models of oxaliplatin-induced peripheral neuropathy (OIPN), paclitaxel-induced peripheral neuropathy (PIPN), streptozotocin-induced diabetic neuropathy, and breast cancer–induced bone pain, ART26.12 produces a dose-dependent reversal of mechanical allodynia and prevents thermal hyperalgesia, while also attenuating chemotherapy-associated weight loss. In an imiquimod-induced psoriasis model, ART26.12 reduces PASI scores and ameliorates epidermal hyperplasia and inflammatory cell infiltration.

Mechanistically, its core mode of action is mediated through lipid modulation (e.g., regulation of N-acyl amino acids in the spinal cord, as well as ceramides and linoleic acid derivatives in the skin), and depends primarily on activation of the cannabinoid receptor 1 (CB₁), with additional involvement of CB₂, TRPV1, and PPARα. ART26.12 also modulates the expression of ion channels in the periaqueductal gray, affects pathways related to epidermal differentiation, and regulates signaling cascades such as NF-κB and PPAR, thereby exerting analgesic, anti-inflammatory, and cell proliferation/differentiation–modulating effects.

References:

[1] Warren G, Osborn M, Tsantoulas C, David-Pereira A, Cohn D, Duffy P, Ruston L, Johnson C, Bradshaw H, Kaczocha M, Ojima I, Yates A, O'Sullivan SE. Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy. J Pain. 2024 Jul;25(7):104470. doi: 10.1016/j.jpain.2024.01.335. Epub 2024 Jan 15. PMID: 38232863.

[2] Warren WG, Osborn M, Duffy P, Yates A, O'Sullivan SE. Potential safety implications of fatty acid-binding protein inhibition. Toxicol Appl Pharmacol. 2024 Oct;491:117079. doi: 10.1016/j.taap.2024.117079. Epub 2024 Aug 31. PMID: 39218163.

[3] Warren WG, Osborn M, David-Pereira A, Tsantoulas C, Xue W, Yates A, OSullivan SE. ART26.12, a novel fatty acid-binding protein 5 inhibitor, shows efficacy in multiple preclinical neuropathy models. Eur J Pain. 2025 Feb;29(2):e4718. doi: 10.1002/ejp.4718. Epub 2024 Aug 26. PMID: 39188040; PMCID: PMC11671339.