The anti-inflammatory drug licofelone [=ML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1<i>H</i>-pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress formation of PGE₂ in various cell-based test systems, but underlying molecular mechanisms are not entirely clear. Here, we examined direct interference with enzymes...

The Kirsten rat sarcoma viral oncogene homologue KRAS is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. approval clinical use of first selective inhibitors G12C mutant therefore holds great promise cancer treatment. However, despite initial encouraging results, overall survival benefit that patients experience following treatment with these has been disappointing to date, pointing toward need develop more powerful...

A series of polysubstituted pyridin-4-yl imidazole inhibitors p38 MAP (mitogen-activated protein) kinase was prepared as small molecular anticytokine agents and drug candidates for the treatment chronic inflammatory diseases. The contribution substituents at pyridinyl moiety to selective inhibition without concomitant cytochrome P450 interaction evaluated. Placement a 1-phenylethyl (7e, p38: IC50 0.38 μM) or acetyl substituent exocyclic nitrogen several 2-aminopyridine imidazoles led...

On the basis of ATP adenine, a series adenine and purine derivatives was prepared tested for their ability to inhibit spectrum disease-related kinases. There has been scant research investigating potential cosubstrate derived kinase inhibitors other kinases than CDKs. Our inhibitor design combined system from original phenyl moieties in order explore possible interactions with different regions binding site several protein have number hits assayed substances, which led us conclude that...

In osteoarthritis (OA), cartilage destruction is associated not only with an Imbalance of anabolic and catabolic processes but also alterations the cytoskeletal organization in chondrocytes, although their pathogenetic origin largely unknown so far. Therefore, we have studied possible effects proinflammatory cytokine IL-1β on components cytoskeleton OA chondrocytes gene expression level. Using a whole genome array, found that involved regulation many cytoskeleton-related genes. Apart from...

In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on pyridinyl unit, using purine bioisosteres structure analogues. identification most potent bioisostere was followed by a further derivatization to address hydrophobic region II. combination with C-2 modifications imidazole core, were able design highly active inhibitors kinase. inhibitor presented herein...

With the objective of pharmacodynamic monitoring immunosuppressive efficacy mycophenolate mofetil (MMF) (CellCept, Hoffman-LaRoche, Grenzach-Wyhlen, Germany), a method for determination inosine monophosphate dehydrogenase (IMPDH) activity in whole blood cell (WBC) lysates and mononuclear cells (MNCs) was developed. The assay is based on incubation WBC or lysed MNCs presence supplemented 5'-monophosphate (IMP) nicotimamide adenine dinucleotide (NAD). formation xanthosine (XMP) determined by...

Summary Background : There is a growing clinical trend to increase the daily dose of mesalazine, which leads significant compliance issues associated with multiple dosings current preparations. Aim To examine gastrointestinal performance and systemic exposure 1.5 g sachet (micropellets) mesalazine formulation, compared three enteric‐coated tablets (500 mg each, Claversal). Methods A randomized, two‐way, cross‐over pharmacoscintigraphic (scintigraphy plus pharmacokinetics) study cross‐over,...

Targeting cytokines has become an important focus in the treatment of many inflammatory disorders. p38 MAP kinase (MAPK) is key enzyme regulating biosynthesis and release pro-inflammatory such as IL-1beta TNFalpha. Inhibition MAPK results decreased expression these cytokines. Tri- tetrasubstituted pyridinylimidazoles are potent inhibitors MAPK. Substitution on pyridinyl moiety allows design that show increased selectivity activity by targeting enzyme's hydrophobic region II. The objective...

A general, easy-to-implement strategy for mapping the structure of organic phases integrated in mesoporous silica drug delivery devices is presented. The approach based on a few straightforward solid-state NMR techniques has no limitations regarding concentrations active compounds and enables discrimination various phases. This way, among range typical arrangements solvent molecules, unique, previously unknown organogel phase self-assembled tapentadol glucofurol as was unveiled clearly...

Prediction of the metabolic profile a potential new drug is recommended at an early stage in industrial discovery process to determine whether or not any potentially reactive toxic metabolites are formed. In present study, we investigated vitro metabolism ML3403 ({4- [5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl -(1-phenylethyl)-amine), potent and selective p38 MAP kinase inhibitor using mouse liver microsomes. The combination LC-ESI-Qq-TOF (tandem quadrupole...

A number of pharmaceutically important drugs contain asymmetric sulfinyl moieties, so the biological evaluation chiral sulfoxides as human drug metabolites is for development safe and effective pharmaceuticals. Asymmetric oxidation one most attractive ways to prepare sulfoxides. In combination with different ligands, iron- titanium-catalyzed oxidations tri- tetrasubstituted 2-thioimidazoles afford corresponding enantiomeric excesses up 99% novel p38α mitogen-activated protein kinase (p38α...

The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition p38α MAPK and phosphodiesterase 4 (PDE4), the benefits arising from blockage both inflammation-related enzymes were thoroughly investigated. most promising compound, CBS-3595 (1), successively evaluated in vitro experiments as well ex vivo preclinical studies after administration 1 rodents, dogs, monkeys. resulting data clearly indicated potent...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStudies on the biosynthesis of aliphatic lactones in Sporobolomyces odorus. Conversion (S)- and (R,S)-13-hydroxy-(Z,E)-9,11-octadecadienoic acid into optically pure (R)-.delta.-decalactoneWolfgang Albrecht, Marion Schwarz, Juergen Heidlas, Roland TresslCite this: J. Org. Chem. 1992, 57, 7, 1954–1956Publication Date (Print):March 1, 1992Publication History Published online1 May 2002Published inissue 1 March...