Type 2 diabetes is a disease that often requires polypharmacy with medications associated with different mechanisms of action to optimize blood glucose control. For this reason, the identification of novel pharmacotherapeutic mechanisms is highly desired. Building on previous studies that demonstrated that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity is the rate-limiting enzyme of ketone oxidation and contributes to the hyperglycemia associated with obesity, researchers have published a new study in Diabetes.
The researchers and faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta (UAlberta) in Edmonton, Canada, have pinpointed the FGA pimozide as a SCOT inhibitor and a therapeutic contender to decrease glycemic control. Using mice and computer modeling, the team was able to conclude that not only pimozide, but also the diphenylbutylpiperidine (DPBP) drug class as a whole, are SCOT inhibitors. Although early speculation may have associated this glucose-lowering effect in obesity with inhibition of D2 receptors, this was not the case.
Lead author, John Ussher, PhD, professor of faculty of pharmacy and pharmaceutical sciences at UAlberta, and colleagues embarked on the journey to determine why the DPBP drugs work. “For the patients who can’t take metformin, patients with late-stage diabetes where their beta cells aren’t working as well, when you’re trying to find new therapies or new combination therapies as the disease progresses, it becomes more important to find new drug classes that target new mechanisms so then you have more options to try and lower blood sugar in those individuals,” Dr. Ussher stated, elaborating further, “We’ve tested three drugs now, and they all interact with this enzyme.” Dr. Ussher also added, “They all improve blood sugar control by preventing the muscle from burning ketones as a fuel source. We believe this SCOT inhibition is the reason these antipsychotics might actually have a second life for repurposing as an anti-diabetic agent.”
Developing completely novel drug agents to market comes with risk in terms of time and money spent. The research team shared that the benefit of repurposing a preexisting drug already available on the market allows scientists to more quickly and more economically zero in on just the safety and efficacy of the new indication. “With something that’s an older drug which we used historically in humans that we no longer use, we know what the adverse effects are, we know in general that it’s safe,” Dr. Ussher commented, adding, “That’s where repurposing comes in. Can we identify the other targets that a drug may interact with, and by identifying those other targets, can this drug serve a purpose for a different disease? As you already have safety data, it somewhat accelerates the process. And from an economic standpoint, often because a lot of these drugs being pursued for repurposing are older, they’re off patent and cheaper.”
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