The Role of Five-Membered Aromatic Rings Containing N and O in Modulating Bile Acid Receptors: An Overview

Abstract

Over the past decades, extensive scientific research in the fields of chemistry and pharmaceutical chemistry has led to the synthesis and study of numerous chemical compounds with diverse therapeutic applications. Many of these compounds feature heterocyclic aromatic structures, including four-, five-, and six-membered rings. Among them, five-membered heteroaromatic rings have garnered particular attention in medicinal chemistry due to their favorable properties, such as enhanced metabolic stability, solubility, and bioavailability, key attributes for the development of effective drugs. The distinctive physicochemical properties and biological activities of five-membered heterocycles have established them as vital structural motifs in numerous clinically effective drugs. These heterocyclic compounds play a crucial role in the design of therapeutic agents, including those targeting bile acid receptors. Bile acid receptor modulators, activated by endogenous bile acids, offer promising potential in treating a variety of metabolic and enterohepatic disorders, such as dyslipidemia, diabetes, cholestasis, and inflammatory bowel disease. This review aims to provide an up-to-date overview of aromatic five-membered nitrogen- and oxygen-containing heterocycles, focusing on their role as bile acid receptor modulators, particularly farnesoid X receptor and G protein-coupled bile acid receptor 1. These receptors are clinically validated targets for the treatment of metabolic disorders and nonalcoholic steatohepatitis.

Keywords: G protein‐coupled bile acid receptors 1; farnesoid X receptors; five‐membered rings; heterocyclic compounds; isoxazole.

Scheme 1

Synthetic routes for the synthesis of 3,5‐ and 3,4,5‐isoxazoles.

Figure 1

Isoxazole‐based derivatives reported as FXR agonists.

Figure 2

5‐Isopropylisoxazole derivatives reported as FXR agonists.

Figure 3

5‐Cyclopropylisoxazole derivatives reported as FXR agonists.

Figure 4

5‐Methylisoxazole derivative (43) and bile acids‐isoxazole hybrids 44 and 45.

Figure 5

Fexaramine derivatives 46 and 47.

Figure 6

Isoxazole‐based FXR antagonists 48–51.

Figure 7

Pentacyclic triterpene‐OA derivatives 52a–52d.

Figure 8

5‐Methyl‐3‐aryl‐4‐isoxazolecarboxamides derivatives 53 and 54.

Figure 9

Lead optimization of 5‐Methyl‐3‐aryl‐4‐isoxazole derivative 55 to give derivatives 56–59.

Figure 10

Regioisomers of oxadiazoles.

Scheme 2

1,3‐Dipolar cycloaddition or Amidoxime route for the preparation of 1,2,4‐oxadiazoles.

Scheme 3

Synthesis of 1,3,4‐oxadiazole building block.

Figure 11

1,2,4‐oxadiazole derivatives 60–62.

Figure 12

Oxadiazole derivatives (63–67) reported in this review.

Figure 13

(1,2,4‐oxadiazol‐5‐yl)pyrrolidin‐3‐yl)ureidyl derivatives 68–69.

Figure 14

Chenodeoxycholic acid (CDCA) derivatives (70–72).

Figure 15

Oxazole‐based FXR modulators.