Repositioning of Omarigliptin as a once-weekly intranasal Anti-parkinsonian Agent

Bassam M Ayoub,Shereen Mowaka,Marwa M Safar,Mariam M Tadros,Haidy E Michel,Mohamed M Elmazar,Shaker A Mousa,Nermeen Ashoush,Mona G Arafa

doi:10.1038/s41598-018-27395-0

Abstract

Drug repositioning is a revolution breakthrough of drug discovery that presents outstanding privilege with already safer agents by scanning the existing candidates as therapeutic switching or repurposing for marketed drugs. Sitagliptin, vildagliptin, saxagliptin & linagliptin showed antioxidant and neurorestorative effects in previous studies linked to DPP-4 inhibition. Literature showed that gliptins did not cross the blood brain barrier (BBB) while omarigliptin was the first gliptin that crossed it successfully in the present work. LC-MS/MS determination of once-weekly anti-diabetic DPP-4 inhibitors; omarigliptin & trelagliptin in plasma and brain tissue was employed after 2 h of oral administration to rats. The brain/plasma concentration ratio was used to deduce the penetration power through the BBB. Results showed that only omarigliptin crossed the BBB due to its low molecular weight & lipophilic properties suggesting its repositioning as antiparkinsonian agent. The results of BBB crossing will be of interest for researchers interested in Parkinson’s disease. A novel intranasal formulation was developed using sodium lauryl sulphate surfactant to solubilize the lipophilic omarigliptin with penetration enhancing & antimicrobial properties. Intranasal administration showed enhanced brain/plasma ratio by 3.3 folds compared to the oral group accompanied with 2.6 folds increase in brain glucagon-like peptide-1 concentration compared to the control group.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disease[1]
Omarigliptin (OG) & trelagliptin (TG) in this study were considered for the first time to test their ability to cross the blood brain barrier (BBB) suggesting OG repositioning to brain disorders based on its BBB crossing, its polypharmacology and potential increasing of glucagon-like peptide-1 (GLP-1) concentration in the brain
Results showed that only OG crossed the BBB efficiently suggesting its possible repositioning as antiparkinsonian agent that will be of interest for researchers interested in Parkinson’s disease

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disease[1]. Glucagon-like peptide-1 (GLP-1) was reported as a potential candidate in modifying neurodegenerative diseases as a promising antiparkinsonian effect of dipeptidyl peptidase (DPP)-4 inhibitors (Gliptins) by exerting a neuroprotective effect in PD animal models[2,3]. A recent study suggested repositioning of teneligliptin to brain disorders[11]. Omarigliptin (OG) & trelagliptin (TG) in this study were considered for the first time to test their ability to cross the blood brain barrier (BBB) suggesting OG repositioning to brain disorders based on its BBB crossing, its polypharmacology and potential increasing of GLP-1 concentration in the brain. De novo drug discovery is a traditional approach, which is costly and time-consuming process. Despite the fact that the initial therapy of diabetes usually be with metformin, thereafter treatment should consider different second line options. These include DPP-4 inhibitors, of which OG and TG are once weekly versions[34,35]. In contrast to the once-daily DPP-4 inhibitors, once-weekly administration can improve patients’ adherence[36,37,38,39,40,41,42,43]

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