GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis

Abstract

GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn’s and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR1 agonists. In vitro pharmacological assays showed that compound 6 selectively activates GPBAR1 (EC50 = 0.3 μM) and reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in THP1 cells. The binding mode of compound 6 in GPBAR1 was elucidated by docking calculations. Moreover, compound 6 protects against TNBS-induced colitis in Gpbar1+/+ rodent model, representing an intriguing lead for the treatment of these inflammatory disorders.

Cholecystectomy-induced secondary bile acids accumulation ameliorates colitis through inhibiting monocyte/macrophage recruitment

“… 54–57 Recent studies reported that HDCA suppressed intestinal epithelial cell proliferation, accompanied by alteration of gut bacteria and BAs profiles, and the HDCA analogs protected against TNBS-induced colitis. 58 , 59 We also confirmed specific secondary BAs (cholecystectomy-accumulated LCA, DCA, or HDCA) ameliorated DSS-induced colitis and accelerated mucosal repair.…”

Structural Basis for Developing Multitarget Compounds Acting on Cysteinyl Leukotriene Receptor 1 and G-Protein-Coupled Bile Acid Receptor 1

“…12−15 Targeting GPBAR1 with agonist molecules has demonstrated being a valid strategy to contrast hepatic inflammation, steatohepatitis, biliary diseases, and metabolic syndromes. 16 In particular, we reported that REV5901 has positive effects in a mouse model of colitis with reduced levels of CysLTs, CysLT 1 R, and cyclooxygenase 1 and 2 in a GPBAR1-dependent manner. 11 These data should be further analyzed considering that the CysLT 1 R antagonist montelukast has shown effect against colitis-associated colon carcinogenesis and inflammation.…”

“…Among these, we have recently reported α-pentyl-3-[2-quinolinylmethoxy] benzyl alcoholREV5901 (Figure )as the first compound endowed with dual activity as CysLT 1 R antagonist and agonist of the G-protein-coupled bile acid receptor 1 (GPBAR1) . The latter is another class A GPCR activated by secondary bile acids and highly expressed in the intestine, gall bladder, brown adipose tissue, muscles, and immune cells. − Targeting GPBAR1 with agonist molecules has demonstrated being a valid strategy to contrast hepatic inflammation, steatohepatitis, biliary diseases, and metabolic syndromes . In particular, we reported that REV5901 has positive effects in a mouse model of colitis with reduced levels of CysLTs, CysLT 1 R, and cyclooxygenase 1 and 2 in a GPBAR1-dependent manner .…”

“…As depicted in Scheme 1, the synthesis of compounds 1−6 started with the ester reduction via DIBAL-H solution of the commercially available methyl quinoline-2-carboxylate (16) and the subsequent Mitsunobu reactions with two different phenols (methyl 4-hydroxybenzoate or methyl 3-hydroxybenzoate) to produce compounds 1 (76% yield) and 4 (78% yield), respectively. Basic hydrolysis and DIBAL-H reduction on methyl esters furnished the corresponding alcohols 2 (68% yield) and 5 (60% yield) and the carboxylic acids 3 (43% yield) and 6 (68% yield).…”

GLP-1 Mediates Regulation of Colonic ACE2 Expression by the Bile Acid Receptor GPBAR1 in Inflammation

“…Since intestinal inflammation differentially modulates ileal and colon expression of ACE2 mRNA in Crohn’s disease patients, we further investigated the mechanisms involved in the regional regulation of ACE2 and focused our attention on the bile acid receptor GPBAR1. GPBAR1 is a bile acid receptor for secondary bile acids, LCA and DCA, that are formed in the colon from enzymatic processing of primary bile acids, CA and CDCA, by the intestinal microbiota [ 10 , 11 , 12 ], We have previously shown that, in addition to exerting potent counter-regulatory effects on intestinal inflammation, and attenuating inflammation-driven immune dysfunction in rodent models of IBD [ 17 , 23 , 47 , 48 , 49 ], bile acids might bind and activate ACE2 [ 50 ], suggesting a potential interaction between these pathways. Additionally, since GPBAR1 agonism attenuates TNF-α production by M1 type intestinal macrophages and promotes IL-10 mRNA transcription, we decided to investigate how GPBAR1 expression is regulated in the terminal ileum and colon of IBD patients and whether this pattern of regulation is integrated with ACE2 mRNA expression.…”