Development of a Safe Mitochondrial Uncoupler, OPC-163493

Mitochondrial uncoupling regulates heat production in cells by preventing energy produced by the electron transport chain from being directed to the production of adenosine triphosphate, an energy store molecule used to power cellular operations. Modestly increased uncoupling mimics some of the benefits of calorie restriction, meaning improved cell function, health, and life span. Greatly increased uncoupling is fatal, due to excessive heat production. Therein lies the challenge when it comes to the production of drugs that can induce mitochondrial uncoupling. Some progress has been made in recent years regarding strategies that lead to safe mitochondrial uncoupling drugs, and there are now a few drug candidates with published data in addition to the one described here.

Obesity, nonalcoholic fatty liver disease (NAFLD), and insulin resistance (IR) associated with visceral, hepatic, or ectopic fat are major risk factors for a number of chronic diseases including diabetes mellitus (DM), cardiovascular diseases, and cancer. These metabolic disorders are intrinsically involved in an energy imbalance between energy expenditure and calorie intake. An appropriate degree of calorie restriction (CR) ameliorates these disorders, and moreover, it is the only proven way to extend lifespan in mammals like rodents. It has already been shown in both primates and rodents that CR improves health, decreases age-related mortality, and extends lifespan.

The mitochondrial uncoupler 2,4-dinitrophenol (DNP) was widely used as a weight-loss agent in the 1930s; however, its use was accompanied by many severe adverse effects including hyperthermia, cataracts, agranulocytosis, and even death. These effects were ascribed to the narrow therapeutic window, and finally the FDA banned its use in 1938. Since then, the use of chemical mitochondrial uncouplers has been confined to their use as reagents for basic research. Nevertheless, there has been a revival in interest in their therapeutic applications, and attempts to discover safe chemical uncouplers have been made due to their energy-consuming benefit. In particular, liver-targeted mitochondrial uncoupling is a promising means of an efficacious and safe treatment for DM and hepatic steatosis.

Our initial screened compound cyanotriazole derivative 1 has a unique chemical structure different from any known mitochondrial uncouplers. We attempted to optimize it as a safe therapeutic option for metabolic disorders such as DM. In this optimization, we regarded safety as the most important factor; therefore, we primarily assessed organ distribution and the acute toxicity of the compounds as well as antidiabetic efficacy. We describe here the optimization process from initial screening hit compound to a liver-localized mitochondrial uncoupler OPC-163493, which recently demonstrated its potent antidiabetic and cardiovascular beneficial effects with acceptable safety.


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