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