What is the clinical significance?
The multi-target drug PTUPB has compelling potential to treat type 2 diabetic complications.
INTRODUCTION
Diabetes is a significant health problem worldwide. Globally 8.5% of adults aged 18 years and older have diabetes and diabetes was the direct cause of 1.6 million deaths in 2016. The high mortality and morbidity associated with diabetes is due to several complications. One of the most common diabetic complications is micro- and macro-vascular dysfunction that results in diabetic nephropathy that progresses to end-stage renal diseases (ESRD) and death (Warren et al., 2019). Approximately 20–40% of diabetic patients develop nephropathy, and due to the growing incidence of diabetes, diabetic nephropathy is now the main cause of ESRD worldwide (Toth-Manikowski and Atta, 2015). Moreover, diabetic nephropathy incidence rates show no signs of slowing. In the USA alone, 42% of all ESRD cases had a diagnosis of diabetic nephropathy (Warren et al., 2019).
Besides glycemic control with anti-diabetic drugs, renin angiotensin system (RAS) blockers have been the standard of care to treat diabetic nephropathy. Unfortunately, approximately one-half of diabetic patients fail to achieve acceptable glycemic control with the currently available anti-diabetic options and RAS blockers have been mildly effective in reducing diabetic nephropathy progression to ESRD. Consequently, morbidity and mortality associated with diabetes is still high because of complications such as hypertension and diabetic nephropathy (Catalá-López et al., 2016; Delanaye and Scheen, 2019). The poor treatment outcome with the present anti-diabetic drugs is also partly due to uncontrolled comorbid risk factors such as dyslipidemia in type 2 diabetes (Patti et al., 2020). Indeed, according to the American Diabetic Association, during the period of 2009-2012 about 65-70% of diabetic patients had pre-existing dyslipidemia and other complications at the time of diagnosis (Afkarian et al., 2013). Thus, there is an urgent need for novel treatments that reduce cardiovascular risk, have a favorable impact on comorbid conditions such as diabetic nephropathy. We suggest that any such novel treatment approach that will target multiple pathologies associated with type 2 diabetes can be molecule with multiple pharmacophores, possibly a bifunctional molecule.
The concept that bifunctional molecules could be developed to treat diseases has been energized by the approval of Entresto, a combined Neprilysin and Angiotensin Type 1 Receptors inhibitor, for heart failure (Chalikias et al. 2020). These multi-target drugs have much more potential than single-target and highly specific agents due to better (i ) disease modifying actions, (ii ) additive and/or synergistic therapeutic actions, (iii ) more predictable pharmacokinetics, (iv ) prolonged duration of effectiveness, and (v ) lower probability for drug interactions. As a result, it is increasingly recognized that a balanced modulation of two targets can provide a superior therapeutic effect and milder side effect profile.
We developed a bifunctional molecule that concurrently inhibits sEH and COX-2. Inhibitor of sEH possess anti-hypertensive, anti-diabetic, anti-inflammatory, and anti-fibrotic actions (Imig, 2018). COX-2 selective inhibitors are widely used to manage inflammation by inhibiting the generation of pro-inflammatory COX metabolites (Nandakishore et al., 2014). Combining sEH inhibition with COX-2 inhibition can limit COX-2 side effects while increasing therapeutic potential to combat organ damage. Moreover, we have found that co-administration of lower doses of COX-2 inhibitors with a sEH inhibitor reduces the potential risk of adverse cardiovascular events (Grosser et al., 2006). Thus, the benefits of each agent in this combination are retained and the mechanism-based adverse effects are attenuated. This synergy provides support to the concept that as a single molecule such as the sEH/COX-2 inhibitor, PTUPB, has therapeutic potential for complex chronic diseases while decreasing the side effects associated with COX-2 inhibitors. In the present study, we investigated therapeutic potentials of PTUPB in a type 2 diabetic nephropathy model and demonstrated its promising effects.
MATERIALs AND METHODs