1,721,080 research outputs found
Modification of semisynthetic bile acid derivatives as human receptor modulators
No full textBile acids (BAs), the end products of cholesterol catabolism, are able to interact with nuclear and membrane endogenous receptors, inducing several cellular networks that regulate lipids, glucose and bile acids homeostasis. Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the major primary bile acids synthesized in human livers, and are conjugated with taurine or glycine for secretion into bile. Two targets of BAs are the endogenous nuclear receptor FXR (farnesoid-X-receptor) and the membrane receptor GPBAR1 (G-protein coupled receptor 1) (1-2) and since their activation is linked to the control of different metabolic and enterohepatic functions, they could be considered efficient targets in the treatment of several human diseases (3-5).
One limit of the therapeutic use of BA derivatives is their promiscuity in binding different receptors and inducing an increase of risk for adverse side effects. In addition, the carboxyl group on the side chain conjugates with taurine and glycine, and the conjugated metabolites undergo to extensive enterohepatic circulation, resulting in the risk of drug accumulation.
In the last years, medicinal chemistry modifications on bile acid scaffolds, mainly performed on chenodeoxycholic acid (CDCA) and focused on the length/functionalization of the side chain, as well as on the tetracyclic core, afforded a large amount of derivatives useful in the treatment of metabolic and enterohepatic disorders, ranging from metabolic syndrome, diabetes, cholestasis and non-alcoholic steatohepatitis.
In this contest, we have manipulated also the scaffold of 6-ethylcholane acid (6-ECDCA), a semi-synthetic bile acid, to obtain potent and selective FXR agonist with improved pharmacokinetic properties
Natural ligands for nuclear receptors: biology and potential therapeutic applications
No full textNuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics. Research in the last two decades has focused to the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases, such as cancer, diabetes, dyslipidemia, fatty liver disease, drug hepatotoxicity and cholestasis. The search for novel NRs agonists and antagonists with enhanced selectivity prompted the exploration of the extraordinary chemical diversity associated to natural products. In recent years a number of natural products were disclosed as ligands of NRs and proved to have remarkable affinity and in some cases peculiar mode of action. In this review the natural ligands of the subfamily NR1, NR2, and NR3 will be described with an emphasis to their mechanisms of action and pharmacological profiles
Reduced order modeling in nonlinear homogenization: A comparative study
No full textComputationally inexpensive nonlinear homogenization methods are much sought after in academia and
industry. However, the accuracy and the accessibility of the methods play an important role. Two
nonlinear homogenization methods for microstructured solid materials are investigated in this work:
the pRBMOR (Fritzen and Leuschner, 2013; Fritzen et al., 2014) and the NUTFA (Sepe et al., 2013).
Both methods are based on ideas of the nonuniform transformation field analysis (NTFA; Michel
and Suquet, 2003, 2004). A detailed comparison with respect to accuracy, storage requirements
and the evolution of the reduced degrees of freedom is carried out. Numerical examples for two- and
three-dimensional problems undergoing nonproportional load paths are presented
Farnesoid X receptor modulators (2011 - 2014): a patent review
No full textFarnesoid-X-receptor (FXR) is the receptor for primary bile acids expressed in enterohepatic tissues where it regulates bile acid uptake, metabolism and disposal. For its role as a bile acid sensor, FXR has been thought to be an important target in the treatment of cholestatic disorders, a family of diseases in which endogenous bile acids accumulate in the body. Cholestasis might occur as a consequence of inborn metabolic errors and three major disorders, intra-hepatic cholestasis in pregnancy, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis account for the vast majority of clinical cholestasis occurring in adulthood. In addition, FXR agonists are gaining attention as potential regulators of lipid and glucose metabolism and therefore as new therapeutical approaches to the treatment of fatty liver disease, type 2 diabetes and obesity
Synthetic studies on homophymine A: stereoselective synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid
No full textAn efficient and highly stereocontrolled synthesis of (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid, the beta-hydroxy acid unit that acylates the N-terminus of homophymine A, has been devised starting from iodoethane and (S,S)-pseudoephedrine propionamide in 9 steps and 36% overall yield. Comparison of the 1H and 13C NMR and optical rotation data of the resulting beta-hydroxy acid with the natural fragment unambiguously verifies the configurational assignment as (2R,3R,4R,6R)
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