Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibitory effect of the clinically used p-carbethoxyphenyl ester of epsilon-guanidino-caproic acid methanesulphonate (epsilon-GCA-CEP) on the catalytic properties of human LYS77-plasmin (EC 3.4.21.7), bovine factor Xa (EC 3.4.21.6), bovine alpha-thrombin (EC 3.4.21.5), ancrod (EC 3.4.21.28), crotalase (EC 3.4.21.30), bovine beta-trypsin (EC 3.4.21.4), porcine pancreatic beta-kallikrein-B (EC 3.4.21.35), human urinary kallikrein (EC 3.4.21.35) and the Mr 54,000 species of human urokinase (EC 3.4.21.31) was investigated (between pH 2.0 and 8.5, I = 0.1 M; T = 21 +/- 0.5 degrees C), and analyzed in parallel with that of the homologous derivative p-carbethoxyphenyl epsilon-amino-caproate hydro chloride (epsilon-ACA-CEP). On lowering the pH from 5.5 to 3.0, values of the apparent dissociation inhibition constant (Ki) for epsilon-GCA-CEP and epsilon-ACA-CEP interaction with the serine proteinases considered increase, reflecting the acidic pK-shift upon inhibitor binding of a single ionizing group. Over the whole pH range explored, (i) epsilon-GCA-CEP interacts with bovine factor Xa and bovine alpha-thrombin with an higher affinity than that observed for epsilon-ACA-CEP binding; (ii) both inhibitors associate to bovine beta-trypsin with the same affinity; and (iii) epsilon-ACA-CEP inhibits human Lys77-plasmin and the Mr 54,000 species of human urokinase with an higher affinity than that reported for epsilon-GCA-CEP association, thus reflecting the known enzyme primary specificity properties. However, the affinity of epsilon-ACA-CEP for ancrod, crotalase, porcine pancreatic beta-kallikrein-B and human urinary kallikrein, all of which preferably bind arginyl rather than lysyl side chains at the primary position of substrates and/or inhibitors, is paradoxically higher than that displayed by epsilon-GCA-CEP. By considering the amino acid sequences, the X-ray three-dimensional structures and/or the computer-generated molecular models of serine proteinase: inhibitor adducts, the observed binding behaviour of epsilon-GCA-CEP and epsilon-ACA-CEP to the enzymes considered has been related to the inferred stereochemistry of proteinase: inhibitor contact region(s).
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PMID:Inhibition of serine proteinases by p-carbethoxyphenyl esters of epsilon-guanidino- and epsilon-amino caproic acid: thermodynamic and molecular modeling study. 272 72

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abarelix, ABX-EGF, ademetionine, agomelatine, AMGN-0007, 9-aminocamptothecin, AN-9, anecortave acetate, anidulafungin, AOD-9604, apolizumab, apomate, L-arginine hydrochloride, arzoxifene hydrochloride; Bevacizumab, BP-897, BufferGel; Capravirine, carboxyamidotriazole, carnosine, CC-4047, CEP-701, cerivastatin sodium, clofarabine, conivaptan hydrochloride, CP-461, CS-003; Daptomycin, darifenacin, decitabine, deferasirox, duloxetine hydrochloride; Eberconazole, Ecyd, efalizumab, eglumegad hydrate, EMD-72000, (-)-epigallocatechin gallate, exatecan mesilate, exenatide; Fampridine, fenretinide, ferumoxtran-10; Gadofosveset sodium, garenoxacin mesilate, genistein, glutamine, GPI-15715; Hexyl insulin M2, human insulin, HYB-165; Indisulam, irofulven; KRN-5500, L-796568, laurocapram, lidocaine/prilocaine, lonafarnib, lotrafiban; Melagatran, melatonin, 2-methoxyestradiol, metreleptin, motexafin gadoliniu, motexafin lutetium; Natalizumab, nelarabine, NO-aspirin, NSC-683864; ONO-6126; Pemetrexed disodium, pexelizumab, pirfenidone, PncCRM9, polyglutamate paclitaxel, pramlintide acetate pregabalin, PRO-2000; Ragaglitazar, ramelteon, rasagiline mesilate, rDNA insulin, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human parathyroid hormone (1-84), reolysin RG228, roflumilast, roxifiban acetate, RPI-4610, rubitecan; Safinamide mesilate, solifenacin succinate, SRL-172; T-138067, tafenoquine succinate, tecadenoson, TER-286, tesaglitazar, tetrathiomolybdate, tezosentan disodium, TheraCIM, tigecycline, tipifarnib, tolvaptan, trabectedin, tributyrin, trimegestone, troxacitabine; UCN-01, urokinase alfa; Vinflunine, viscum fraxini 2; Xcellerated T cells, ximelagatran.
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PMID:Gateways to clinical trials. 1468 3

Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore be involved in astrocyte inflammation. In this study, we explored the effect of the MLK inhibitors CEP-1347 and CEP-11004 on the activation of murine astrocytes by either TNF plus IL-1 or by a complete cytokine mix containing additional IFN-gamma. The compounds blocked NO-, PG-, and IL-6 release with a median inhibitory concentration of approximately 100 nM. This activity correlated with a block of the JNK and the p38 pathways activated in complete cytokine mix-treated astrocytes. Although CEP-1347 did not affect the activation of NF-kappaB, it blocked the expression of cyclooxygenase-2 and inducible NO synthase at the transcriptional level. Quantitative transcript profiling of 17 inflammation-linked genes revealed a specific modulation pattern of astrocyte activation by MLK inhibition, for instance, characterized by up-regulation of the anti-stress factors inhibitor of apoptosis protein-2 and activated transcription factor 4, no effect on manganese superoxide dismutase and caspase-11, and down-regulation of major inflammatory players like TNF, GM-CSF, urokinase-type plasminogen activator, and IL-6. In conclusion, MLK inhibitors like CEP-1347 are highly potent astrocyte immune modulators with a novel spectrum of activity.
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PMID:Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347. 1529 95