Poudel Sagun, Qin Chaolong, Pangeni Rudra, Hu Ziwei, Berkbigler Grant, Gunawardena Madeline, Duerfeldt Adam S, Xu Qingguo
Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA.
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55414, USA.
Biomolecules. 2025 Jul 30;15(8):1101. doi: 10.3390/biom15081101.
Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box-Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies.
过氧化物酶体增殖物激活受体α（PPARα）是脂质代谢的关键调节因子，这使其激动剂成为包括慢性周围神经病变在内的各种疾病的重要治疗靶点。现有的PPARα激动剂存在选择性差、生物利用度欠佳和安全性问题等局限性。我们之前证明，新型、强效且具有选择性的PPARα激动剂A190作为一种非阿片类治疗药物，可有效缓解化疗引起的周围神经病变和弗氏完全佐剂诱导的炎性疼痛。然而，单独的A190存在溶解度和渗透性问题，限制了其口服给药。为克服这一挑战，在本研究中，合成了A190的四种新一代酯前药：A190-PD-9（甲酯）、A190-PD-14（乙酯）、A190-PD-154（异丙酯）和A190-PD-60（环状碳酸酯），并对其酶促生物转化和化学稳定性进行了评估。主要候选药物A190-PD-60进一步被制成微乳剂（A190-PD-60-ME），并通过Box-Behnken设计进行优化。A190-PD-60-ME具有纳米级液滴（约120 nm）、低多分散性（PDI<0.3）和高载药量（>90%），人工膜渗透性显著提高。至关重要的是，大鼠体内药代动力学评估表明，与A190-PD-60分散体相比，A190-PD-60-ME的Cmax高16.6倍（439 ng/mL），相对口服生物利用度提高了5.9倍。这些发现支持了前药-微乳剂联合方法作为一种有前景的策略，可克服口服生物利用度挑战并推进PPARα靶向治疗。
