Development of farnesol receptor agonist LJN452: application examples of conformational restriction strategies

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In 1995, two independent research teams in the United States simultaneously discovered a new type of nuclear receptor, which can be weakly activated by the intermediate farnesoid of the mevalonic acid pathway, so it was named "FarnesoidX Receptor (FarnesoidX).

Figure 1.

In the liver, FXR mainly regulates the synthesis and transport of bile acids and the expression of genes related to sugar and lipid metabolism.

Based on the above research conclusions, FXR is a potential target for liver disease and fat metabolism, such as cholestasis-related diseases and non-alcoholic steatohepatitis (NASH).

Figure 2 FXR agonist

In view of the significant physiological regulation of FXR, many pharmaceutical giants have participated in the development of FXR agonists, such as Eli Lilly, GSK, and Novartis.

Discovery of Isoxazole FXR Agonists

Figure 3 Isoxazole non-steroidal FXR agonists

In 2000, GSK obtained the non-bile acid isoxazole FXR agonist GW4064 through the screening of a compound library with a sample of 9000 and a non-cell-binding sensitivity test.

Figure 4 Preliminary optimization of GW4064

The conformational rigidity of the stilbene structure is the key to the agonistic effect.

In order to simplify the synthesis difficulty, four dechlorinated naphthalene-containing compounds AD were prepared.

GSK8062 performed well in in vitro tests, its activity was similar to that of GW4064, but the photostability was greatly improved.

Figure pentanaphthalene ring heterocyclicization

In view of the above-mentioned problems, azalation of the naphthalene ring is an ideal optimization strategy.

Figure 6 Heterocyclic substitution of the carboxyl moiety

Although the PK of GSK2324 has been greatly improved compared to GSK8062, the activity has not been improved much.

Figure 7 EliLilly Isoxazole FXR Inhibitor

Eli Lilly developed a piperidine ring-containing isoxazole FXR agonist LY2562175 on the basis of GW4064 and other related studies.

Figure 8 Novartis benzothiophene full agonist

When Novartis optimized this type of FXR agonism, it retained the piperidine ring in LY2562175 and replaced the previous methylindole with benzothiophene to obtain a full agonist C1 (Figure 7), whose activity is increased compared to GW4064 It has more than doubled, and also solved the problem of partial excitement of LY2562175, but the plasma clearance rate of C1 is high and the oral bioavailability is extremely low (6%).

Figure 9 2,6-Dichlorobenzene optimization

In the optimization of lipophilicity and metabolic stability, fluorine substitution is a common way.

Figure 10 Activity optimization

After improving the metabolic stability, the activity of C4 is similar to that of GW4064.

At present, compound C7 (LJN452) has been advanced to the second phase of clinical study, mainly for cholestatic liver disease and non-alcoholic fatty liver.

to sum up

This article briefly introduces the development process of the FXR agonist LJN452 and the application of the molecular conformational rigid design strategy in its development.
From the initial lead compound GW4064 to the later candidate drug LJN452, it can be described as a twists and turns, and the design conveyed therein The idea is worth learning, and we also hope that LJN452 will be successful in subsequent clinical trials.
After all, there are relatively few drugs available for liver-related diseases, especially non-alcoholic fatty liver disease!

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