MK3102 (Omarigliptin) is a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor (IC50: 2.2 nM) developed for the treatment of type 2 diabetes [1,2]. MK3102 crossed the blood brain barrier (BBB) due to its low molecular weight and lipophilic properties [3].
MK3102 (3, 10, 30, and 50 µM, 4 h) pretreated PC12 cells were attenuated 6-OHDA (50 µM, 24h) - or rotenone (1 µM, 24h) - induced cytotoxicity. MK3102 inhibited the 6-OHDA- or rotenone-induced production of intracellular ROS in PC12 cells [4]. MK3102 decreased the 6-OHDA- and rotenone-induced IκBα phosphorylation and nuclear translocation of NF-κB, resulting in reduced production of the inflammatory mediator NO and iNOS expression [4]. MK3102 suppressed the release of HMGB-1, and decreased the permeability of endothelial monolayer in bEnd.3 brain endothelial cells [1].
MK3102 has a long half-life (rat, 11 h; dog, 22 h) and lower clearance (rat, 1.1 mL min-1 kg-1; dog, 0.9 mL min-1 kg-1) in preclinical species [5]. Concentration of MK3102 in rats' plasma (5 mg/kg, after 2 h, p.o) were found to be 2688.79 ng/mL, MK3102 crossed the BBB after the oral administration showing concentration of 621.75 ng/g in brain tissue. Intra-nasal administration of OG showed significant higher brain/plasma concentration ratio of 0.76 enhancing the ratio by 3.3 folds compared to the oral route [3]. MK3102 (5 mg/kg/d) suppressed the release of inflammatory factors in the brains of LPS-Stimulated mice and protected the BBB integrity destroyed by LPS stimulation [1].
References:
[1]. Du H, Wang S. Omarigliptin Mitigates Lipopolysaccharide-Induced Neuroinflammation and Dysfunction of the Integrity of the Blood-Brain Barrier. ACS Chemical Neuroscience. 2020 Nov 25;11(24):4262-9.
[2]. Hussain H, Abbas G, Green IR, Ali I. Dipeptidyl peptidase IV inhibitors as a potential target for diabetes: patent review (2015-2018). Expert opinion on therapeutic patents. 2019 Jul 3;29(7):535-53.
[3]. Ayoub BM, Mowaka S, Safar MM, Ashoush N, Arafa MG, Michel HE, Tadros MM, Elmazar MM, Mousa SA. Repositioning of omarigliptin as a once-weekly intranasal anti-parkinsonian agent. Scientific Reports. 2018 Jun 12;8(1):8959.
[4]. Gouda NA, Cho J. Omarigliptin Mitigates 6-Hydroxydopamine-or Rotenone-Induced Oxidative Toxicity in PC12 Cells by Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Actions. Antioxidants. 2022 Sep 28;11(10):1940.
[5]. Biftu T, Sinha-Roy R, Chen P, Qian X, Feng D, Kuethe JT, Scapin G, Gao YD, Yan Y, Krueger D, Bak A. Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes.