IMMD, Inc.

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a target for treating metabolic syndrome, whereas there is no PPARδ agonist in clinical use. Previously, we have reported the discovery of 2-(1-piperidinyl)-1,3-benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening techniques. In this study, we performed the further optimization study of the lead compound 1 focusing on improvement of hydrophobic interactions in the binding site to enhance agonist efficacy for PPARδ and subtype selectivity, thereby discovering a novel PPARδ agonist 5g which exhibited high in vitro agonist activity (hPPARδ, EC₅₀ = 4.1 nM) and sufficiently high selectivity ratio over PPARα and PPARγ. Moreover, 5g revealed a significant upregulation of high-density lipoprotein cholesterol level in vivo.

Novel PPARδ agonists, 2-(1-piperidinyl)-1,3-benzothiazole derivatives were discovered by our proprietary docking-based virtual screening technique. Compound 1 as the initial hit was effectively modified to acquire PPARδ agonist activity, resulting in the discovery of compound 12 with high agonistic potency for PPARδ and selectivity over PPARα and PPARγ. Compound 12 also had good ADME profiles and showed in vivo efficacy as a lead.

Nuclear factor-kappa B (NF-κB) transcription factor plays a critical role in regulating radiation-induced inflammatory and immune responses. Intracellular reactive oxygen species generation induces the activation of NF-κB via the inhibitor of κB (IκB) kinase (IKK) complex signaling. Previous studies have reported that the inhibition of IKK-driven NF-κB activation offers a therapeutic strategy for managing inflammatory disorders and various cancers, but it has additionally been reported that treatment targeting NF-κB also shows a radioprotective effect. IMD-0354 is an IKKβ inhibitor that blocks IκBα phosphorylation in the NF-κB pathway. This compound is known to exert anti-inflammatory and antitumor effects, but its radioprotective effects are unclear. Therefore, in the present study, we examined whether or not IMD-0354 has a mitigative effect on radiation-induced damages in mice. IMD-0354 was dissolved in soybean oil and subcutaneously administered to C57BL/6J Jcl mice for 3 consecutive days after 7 Gy of whole-body X-irradiation. The survival rate on day 30 and the NF-κB p65 and IκBα in bone marrow and spleen cells based on flow cytometry were assessed. IMD-0354 administration significantly suppressed the lethality induced by whole-body X-irradiation, and the survival rate increased by 83%. The NF-κB p65 and IκBα in bone marrow and spleen cells were significantly lower in IMD-0354-treated mice than in irradiated mice, suggesting that the IKKβ inhibitor IMD-0354 exerts a radiomitigative effect by suppressing the NF-κB.