A collection of over 50,000 functionally annotated drugs, clinical candidates, and endogenous ligands was docked in silico against nine binding sites from seven protein targets, representing diverse function and structure, namely the sulfotransferases SULT1E1 and SULT1A3, the histone methyltransferase EHMT1, the histone acetyltransferase MYST3, and the nuclear hormone receptors ERalpha, PPARgamma, and TRbeta. For 5 of the 9 virtual screens, compounds that docked best to the receptors clearly recapitulated known biological functions of the genes or identified novel biology subsequently validated in a separate experimental study. In two cases, the hit list indicated some relevant but isolated biological functions which would probably have been ignored a priori, and selected compounds were completely unrelated to gene function for the last two virtual screens. This study demonstrates that virtual screening of pharmacologically annotated compound libraries can be used to derive target biology.

01 Mar 2009·Japanese Journal of OphthalmologyQ3 · MEDICINE

Antiglaucoma drug GLC756 and its effect on cellular cAMP and tumor necrosis factor α release in vitro of activated human monocytic leukemia cells

Q3 · MEDICINE

Article

Author: Cazaubon, Cecile ; Markstein, Rudolf ; Laengle, Ulrich W ; Roman, Danielle

PURPOSEGLC756, a putative antiglaucoma drug with dopamine D(2) agonist and D(1) antagonist properties, significantly decreases tumor necrosis factor alpha (TNF-alpha) levels in lipopolysaccharide (LPS)-induced rats. The present study describes the effects of GLC756 on cellular adenosine 3', 5'-cyclic monophosphate (cAMP) in relation to TNF-alpha production on LPS-stimulated human acute monocytic leukemia cells.METHODSA human peripheral blood acute monocytic leukemia cell line (THP-1) was activated via LPS. THP-1 cells were incubated with GLC756 or betamethasone (positive control) at concentrations of 1, 10, and 30 microM. The TNF-alpha concentration in supernatant and cAMP levels in cellular extract were measured by enzyme-linked immunosorbent assay 0,1, 2.5, 4.5, 7, and 24 h post-activation.RESULTSCompared with LPS controls, both GLC756 at 30 muM and betamethasone at > or =1 microM had a significant inhibitory effect on TNF-alpha release from THP-1 cells 2.5 to 24 h post-activation. Parallel to the TNF-alpha decrease, GLC756 induced significant increases of cellular cAMP 2.5 and 7 h post-activation. Betamethasone had no effect on the cellular cAMP level.CONCLUSIONIntracellular signaling pathway leading to inhibition of the production of the proinflammatory cytokine TNF-alpha after GLC756 treatment might be mediated through the second messenger cAMP.

01 Sep 2007·Clinical & Experimental OphthalmologyQ3 · MEDICINE

Effects of latanoprost, timolol and GLC756, a novel dopamine D₂ agonist and D₁ antagonist on LTC₄ release after rat mast cell activation

Q3 · MEDICINE

Article

Author: Dominique Pralet ; Ulrich W Laengle ; Wolfgang Seewald ; Rudolf Markstein ; Danielle Roman

AbstractPurpose: Mast cells participate in ocular allergic inflammation by releasing biologically active mediators. Leukotrienes are released from activated mast cells via an IgE‐dependent mechanism, and play a crucial role in ocular allergic inflammation. In this study, the effect of three topical antiglaucoma drugs, that is, latanoprost, timolol and GLC756, a novel dopamine D2 agonist and D1 antagonist, on leukotriene C4 (LTC4) release after rat mast cell activation was examined.Methods: A rat basophilic leukaemia RBL‐2H3 mast cell line was activated via IgE/anti‐IgE. Rat mast cells were incubated with latanoprost, timolol, or GLC756 at concentrations of 0.1, 1, 10 and 30 μM. LTC4 concentration in supernatant was assessed 5 h post activation by EIA.Results: Compared with controls, timolol showed no relevant effect on LTC4 release, 5 h after mast cell activation. Latanoprost and GLC756, in contrast, revealed an inhibitory effect on LTC4 release, which was dose‐related and statistically significant at the concentrations of 10 and 30 μM.Conclusion: The results of this study suggest that timolol has no significant influence on LTC4 release from activated mast cells. By contrast, latanoprost and GLC756 inhibited LTC4 release, suggesting a possible anti‐inflammatory effect on ocular allergic inflammatory processes in topical glaucoma medication.

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma	Phase 1	-	Novartis Pharma AG	-
Glaucoma	Phase 1	Switzerland	Novartis AG	-

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