The long-term goal of this project is to develop a safe and efficacious therapeutic small molecule for treatment of acute kidney injury (AKI). AKI results from diverse insults such as sepsis, ischemia-reperfusion (I/R) or nephrotoxicant exposure and nearly half of those who develop AKI do not survive. Since treatment remains largely palliative and survival rates have remained unchanged for several decades, new therapeutic approaches are desperately needed. The role of mitochondrial dysfunction in animal models of AKI has been validated, but there is no approved therapeutic that specifically targets mitochondrial biogenesis (MB) to stimulate mitochondrial function and restore renal function. We have recently published a proof-of-principle study using the ?2-adendergic receptor agonist formoterol that demonstrates stimulation of MB restores mitochondrial function and accelerates recovery from AKI in a murine model (Jesinkey et al., JASN-2013-09-0952). Lasmiditan, a 5-HT1F receptor agonist, is a novel methylpiperidinyl- benzamide that is in phase II clinical trials for treatment f migraines. It should be noted that lasmiditan has CNS-related adverse events. We discovered that lasmiditan is also a potent inducer of MB in renal proximal tubular cells. We also identified an analogue of lasmiditan (aza-lasmiditan) in which the piperidine ring is replaced with a 1,4-piperazine ring that is an equally potent inducer of MB. Aza-lasmiditan is a new chemical entity (NCE) that is not captured in the lasmiditan composition of matter patents. Aza-lasmiditan is also synthesized in 2 steps, as opposed to the 6-step lasmiditan synthesis. We hypothesize that potent aza- lasmiditan analogues that stimulate MB with limited CNS penetration can be used to treat AKI.
In Aim 1 we will synthesize 30-50 aza-lasmiditan analogues that will be modified to maintain MB activity while reducing CNS exposure via changes in polarity and/or attachment of cleavable renal-targeting moieties. The analogues will be tested for receptor binding and MB activity in an in vitro primary renal cell assay.
In Aim 2 structurally diverse analogues that are particularly potent and/or efficacious will initially be injected i.v. into mice to determine MB efficacy in kidney and brain, serum half-life, and CNS concentrations In Phase II, these compounds will be tested for efficacy in murine models of AKI.