An international group of scientists headed by SPbU Prof Mikhail Krasavin has found an alternative to Takeda’s fasiglifam, an anti-diabetic medication produced in Japan which had been considered as the most effective anti-diabetic drug in type 2 diabetes, but turned out to have a serious side effect such as hepatotoxicity. The research findings have been published in European Journal of Medicinal Chemistry.

Anti-diabetic medicines are either not efficient enough or can decrease blood sugar below normal level, and one of the factors linked to a greater risk of hypos is an inaccurate dose of medication.

In 2003, we saw the first glimmerings of hope in anti-diabetes medication, when scientists proved that free fatty acids in blood regulate insulin secretion from pancreatic beta cells through GPR40. With GPR40 as a therapeutic target, medication stabilise blood sugar levels leading to a decrease of receptors in pancreatic beta cells and consequently stops working, thus preventing blood sugar level from dropping below a normal range. So, it can manage drug concentration in blood.

In early 2000s, quite a number of pharmaceutical companies started to develop GPR40 activators. In the lead was Japan’s Takeda Pharmaceutical Company that produced an anti-diabetic drug (fasiglifam). It was tested in a phase III clinical trial and proved to be the most effective in diabetes treatment. However, as early as December 2013, the company announced that it had discontinued fasiglifam global clinical development programme due to its concerns about liver safety as data emerging from all the clinical trials revealed idiosyncratic hepatotoxicity in some patients. By the current costs to developing new drugs of about $1 bln, the losses are massive.

Liver toxicity is primarily associated with high lipophilicity, although it is lipophilicity that imitates fatty acids and activates GPR40. How to make drugs less lipophilic and more polar by preserving the therapeutic target (GPR40) was for SPbU group of scientists to solve. The group headed by Mikhail Krasavin carried out a research under the RNF grant and discovered an unprecedented solution.

The scientists were inspired by the unique properties of the Eli Lilly’s drug LY2881835 as it contains spirocyclic tertiary amine periphery, which reduces the overly lipophilic character of the GPR40 agonists. With Queens University Belfast the scientists used computer-based simulation methods and revealed that a protein molecule contains a “pocket” to comprise polar heterocyclic fragments, which binds an agonist to its receptor.  – We have combined polar fragments and spirocyclic amine and discovered a compound with an increased polarity, comparing to fasiglifam, and high affinity to GPR40, - said Mikhail Krasavin.

Learn more at: Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835 (http://www.sciencedirect.com/science/article/pii/S0223523417300053), European Journal of Medicinal Chemistry.