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Diabetes therapy: the weaponry enlarges with possibilities

A new class of drugs for diabetes and for obesity dependent on it will soon be available. This is judged by the findings of various research groups, which have focused on the metabolism of fats and intestines. The new drugs will simulate the abundant presence of short chain fatty acids (SCFA) that are formed in the intestine thanks to a diet rich in fiber and probiotics. It all started in 2003 when it was discovered that SCFAs were not simple metabolites, but were recognized by cell receptors. An orphan receptor (without known binder), GPR40, it was found that it could bind these acids with good affinity. For the discovery, the research team gained the publication in the prestigious journal Nature (Itoh Y et al., 2003). A few years later, it was possible to demonstrate that the GPR40 activated by SCFA could condition insulin secretion from the pancreas directly, ie pancreatic beta cells possessed this receptor (Salehi A et al., 2005; Schnell S et al., 2005). In the same year, a further group of researchers tested the link between GPR40 and hepatic steatosis in mice suffering from experimentally induced insulin resistance (Steneberg P et al., 2005). Finally the following year the first non-SCFA compounds were identified able to synthetically activate the GPR40 receptor (Garrido DM et al., 2006).

Research is not stopped at the first identified compounds; it continued with the study of natural substances or current drugs that could be able to have the same properties. And the predictions were not wrong, as an independent group found that a class of drugs (fibrates) used to lower triglycerides, have good agonist action for the GPR40 receptor in mice and in diabetic and / or genetically obese rats (Song f et al., 2007). In 2008 the TUG-424 was patented, the first agonist of GPR40 able to induce insulin secretion in laboratory animals. The molecule proved to be very potent, succeeding in secreting insulin with plasma concentrations around 100 nanomolar. The same group has more recently shown that conjugated linoleic acid (CLA) and its isomers can stimulate the GPR40 receptor in pancreatic beta cells. Then two other molecules came out, TAK-875 and AMG 837, which have reached clinical trials and TAK-875 has been shown to improve glycemic control in type 2 diabetic patients. However, Phase III clinical trials involving TAK- 875 were recently discontinued due to signs of liver toxicity in patients.

Despite this setback, the GPR40-based therapies represent an interesting alternative in the discovery of new antidiabetic drugs. The list has grown in the last 5 years, adding names like GW9508, TUG-469, TUG-770, DC206216, CNX-011-67, etc. These substances have been literally “engineered” to the computer through sophisticated programs of “chemical and virtual modeling”, with the sole purpose of avoiding the problem referred to above, ie the appearance of side effects during clinical trials. The molecules discovered originally, in fact, had a good affinity or power, but were exempt from absolute specificity or however very high. From these guided simulations, AS-5759 was developed in 2014, which is a selective receptor agonist and also has the merit of working in concert with the antidiabetic drug sitagliptin (Tanaka H et al., 2014). In genetically obese (db / db) or diabetic (Zucker) mouse models, these experimental drugs have been able to improve residual insulin secretion, improve the glycemic profile, inhibit the production of glucagon and control that of the digestive hormones cholecystokinin and incretin. .

These additional effects have not been judged as unimportant, since especially in type 2 diabetes the digestive hormone pattern is completely subverted. Finding a drug that shows the balance in insulin secretion, but also in the entire intestinal panorama, can improve the management of glycemia even in overweight situations, frank obesity and always in the most frequent situation of insulin resistance. The CNX has already been tested on type 2 diabetic patients, while in 2016 the AM-3189 was synthesized, derived from the previous AM 839 which has the advantage of not penetrating almost in the nervous system, avoiding many side effects. Last year three new compounds were synthesized that will undergo a pre-clinical evaluation for the treatment of type 2 diabetes (Hamdouchi H et al., 2016). This year the last candidates are MR1704 and MK-8666; the latter is already in preliminary evaluation in type 2 diabetic patients.

Failures do not mean abandoning the goal. Perseverance is the key for the results will always come.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Itoh Y et al. Nature. 2003 Mar 13; 422(6928):173-76.

Salehi A et al. Cell Tissue Res. 2005 Nov; 322(2):207-15.

Steneberg P et al. Cell Metab. 2005 Apr; 1(4):245-58.

Schnell S et al. Mol Cell Endocrinol. 2007; 263(1-2):173-80.

Sasaki S et al. J Med Chem. 2011 Mar 10; 54(5):1365-78.

Leifke E et al. Clin Pharmacol Ther. 2012 Jul; 92(1):29-39.

Negoro N et al. J Med Chem. 2012 Apr 26; 55(8):3960-74.

Sunil V et al. BMC Pharmacol Toxicol. 2014 Mar 25;15:19.

Hamdouchi C et al. Med Chem. 2016; 59(24):10891-916.

Peng XV et al. Diabetes Obes Metab. 2017;19(8):1127-34.

Tsuda N et al. Pharmacol Res Perspect. 2017 Aug; 5(4).

Krug AW et al. Clin Transl Sci. 2017 Sep ;10(5):404-411.

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