Semisynthetic bile acids: a new therapeutic option for metabolic syndrome. (August 2019)

• Record Type: Journal Article
• Authors: Lazarević, Slavica; Đanić, Maja; Goločorbin-Kon, Svetlana; Al-Salami, Hani; Mikov, Momir
• Is Part Of: Pharmacological research. Volume 146(2019)
• Publication Date: 2019-08
• Subjects: ACC1 acetyl-CoA carboxylase 1 -- ASBT apical sodium-dependent bile salt transporter -- BSEP bile salt export pump -- CA cholic acid -- CAR constitutive androstane receptor -- CDCA chenodeoxycholic acid -- CMC critical micellar concentration -- CYP7A1 cholesterol-7α-hydroxylase -- CYP8B1 sterol-12α-hydroxylase -- DCA deoxycholic acid -- FAS fatty acid synthase -- FGF19 fibroblast growth factor 19 -- GLP-1 glucagon-like peptide-1 -- I-BABP ileal bile-acid-binding protein -- INT-767 6α-ethyl-3α7α, 23-trihydroxy-24-nor-5ß-cholan-23-sulfate -- INT-777 6α-ethyl-23S-methylcholic acid S-EMCA -- LCA lithocholic acid -- MRP2 multidrug resistance-associated protein 2 -- MRP3 multidrug resistance-associated protein 3 -- MRP4 multidrug resistance-associated protein 4 -- MSy metabolic syndrome -- 12-MKC 12-monoketocholic acid -- NAFLD nonalcoholic fatty liver disease -- NASH nonalcoholic steatohepatitis -- NCX-1000 2-(acetyloxy)-benzoic acid-3-(nitrooxymethyl)-phenyl ester -- NF-kB nuclear factor kB -- NorECDCOH 6α-Ethyl-3α7α-dihydroxy-24-nor-5β-cholan-23-ol -- NorUDCA 24-nor-ursodeoxycholic acid -- NTCP Na - taurocholatepolypeptide -- OATP organic anion transporter -- OCA obeticholic acid -- OSTα/OSTβ organic solute transporter -- PBC primary biliary cholangitis -- PSC primary sclerosing cholangitis -- SHP small heterodimer partner -- SREBP1c sterol regulatory element-binding protein -- T1DM type 1 diabetes mellitus -- T2DM type 2 diabetes mellitus -- TGR5 Takeda G-protein receptor-5 -- UDCA ursodeoxycholic acid; Chemical compounds studied in this article obeticholic acid (PubChem CID: 447715) -- INT-767 (PubChem CID: 23712772) -- INT-777 (PubChem CID: 45483949) -- 3, 7-dihydroxy-12-oxocholanoic acid (PubChem CID: 94235) -- 24-nor-ursodeoxycholic acid (PubChem CID:22845702); Bile acid -- Metabolic syndrome -- Diabetes -- Dyslipidemia -- FXR -- TGR5; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104333
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Bile acids are endogenous emulsifiers synthesized from cholesterol having a peculiar amphiphilic structure. Appreciation of their beneficial effects on human health, recognized since ancient times, has expanded enormously since the discovery of their role as signaling molecules. Activation of farnesoid X receptor (FXR) and Takeda G-protein receptor-5 (TGR5) signaling pathways by bile acids, regulating glucose, lipid and energy metabolism, have become attractive avenue for metabolic syndrome treatment. Therefore, extensive effort has been directed into the research and synthesis of bile acid derivatives with improved pharmacokinetic properties and high potency and selectivity for these receptors. Minor modifications in the structure of bile acids and their derivatives may result in fine-tuning modulation of their biological functions, and most importantly, in an evasion of undesired effect. A great number of semisynthetic bile acid analogues have been designed and put in preclinical and clinical settings. Obeticholic acid (INT-747) has achieved the biggest clinical success so far being in use for the treatment of primary biliary cholangitis. This review summarizes and critically evaluates the key chemical modifications of bile acids resulting in development of novel semisynthetic derivatives as well as the current status of their preclinical and clinical evaluation in the treatment of metabolic syndrome, an aspect that is so far lacking in the scientific literature. Taking into account the balance between therapeutic benefits and potential adverse effects associated with specific structure and mechanism of action, recommendations for future studies are proposed.