Small molecular anti-cytokine agents.
The recent successful introduction of the anti-cytokine biologicals Etanercept, Infliximab, Adalimumab, and Anakinra has stimulated the search for anti-cytokine small-molecules. A number of molecular targets have been identified for the development of such small molecular anti-cytokine agents. The focus of this review will be on those inhibitors of cytokine production, which target either p38 mitogen activated protein (MAP) kinase, TNF-alpha converting enzyme (TACE), or IL-1beta converting enzyme (ICE). P38 MAP kinase occupies a central role in the signaling network responsible for the upregulation of proinflammatory cytokines like interleukin 1beta (IL-1beta) and TNF-alpha, and regulates their biosynthesis at both the transcriptional and translational level. TACE and ICE are two proteases required for the processing of proTNF-alpha and proIL-1beta, respectively into their mature, proinflammatory form. Since the mid-1990s, a plethora of inhibitors of p38 MAP kinase, TACE, and ICE has been characterized in vitro, and individual representatives from all three inhibitor classes have in the meantime been advanced into clinical trials. This review will highlight the correlation between effective inhibition at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta, production. Structure-activity relationships (SAR) will be discussed regarding activity at the respective enzyme target, but also with regard to properties required for efficient in vitro and in vivo cellular activity (e.g., oral availability, solubility, cell penetration, etc.).
Wagner
Gerd
G
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, NR4 7TJ, England.
Laufer
Stefan
S
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D061945:Caspase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013386:Succinates / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014508:Urea / Q000031:analogs & derivatives; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D061945:Caspase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D016207:Cytokines; D006877:Hydroxamic Acids; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D013386:Succinates; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C096429:L 709049; D014508:Urea; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C093642:SB 203580; C464966:VX-745