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Hrvacic B.,Galapagos Research Center Zagreb Ltd | Situm K.,University of Zagreb | Duric K.,Polyclinic Sunce | Bosnjak B.,Medical University of Vienna | And 4 more authors.
Drug and Chemical Toxicology | Year: 2015

Although inhaled glucocorticoids are known to have systemic effects on bone metabolism, there is little comparative information on their relative potencies. The effects of three standard glucocorticoids in causing changes in bone metabolism and growth, therefore, were investigated in relation to other systemic effects in the rat. Given to male Sprague-Dawley rats, 4.5-5.5 weeks old, subcutaneously (s.c.), at doses of 0.3-10 mg/kg daily for 7 days, beclomethasone dipropionate, prednisolone and ciclesonide all dose-dependently inhibited thymus body mass index (BMI) (by 57%, 44% and 76% at 3 mg/kg). Ciclesonide, potently and prednisolone, less effectively, also repressed femoral bone growth (by 41% and 18% at 10 mg/kg), significantly reducing body weight gain (both by 100% at 10 mg/kg), and serum concentrations of acid phosphatase (ACP) and tartarate resistant acid phosphatase (TRACP) (by >30% at 10 mg/kg); both increased serum glucose and triglycerides levels. Serum alkaline phosphatase (ALP) was not affected. Beclomethasone dipropionate had little or no effect on these additional variables. In conclusion, ciclesonide showed pronounced bone growth inhibiting activity after s.c. administration to the rat while other two glucocorticoids showed differences in activity on bone metabolism. However, this model is sufficiently sensitive and specific for testing the effect of glucocorticoids on bone metabolism. © 2014 Informa Healthcare USA, Inc. Source

Hutinec A.,Glaxosmithkline | Hutinec A.,Galapagos Research Center Zagreb Ltd | Rupcic R.,Glaxosmithkline | Rupcic R.,Galapagos Research Center Zagreb Ltd | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

A series of 15-membered azalide urea and thiourea derivatives has been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (D6), chloroquine/pyremethamine resistant (W2) and multidrug resistant (TM91C235) strains of Plasmodium falciparum. We have developed an effective automated synthetic strategy for the rapid synthesis of urea/thiourea libraries of a macrolide scaffold. Compounds have been synthesized using a solution phase strategy with overall yields of 50-80%. Most of the synthesized compounds had inhibitory effects. The top 10 compounds were 30-65 times more potent than azithromycin, an azalide with antimalarial activity, against all three strains. © 2011 Elsevier Ltd. All rights reserved. Source

Kraljevic T.G.,University of Zagreb | Klika M.,University of Zagreb | Kralj M.,Ruder Boskovic Institute | Martin-Kleiner I.,Ruder Boskovic Institute | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

The synthesis of the novel 5-alkyl pyrimidine derivatives, 5,6-dihydrofuro[2,3-d]pyrimidines and 5-alkyl N-methoxymethyl pyrimidine derivatives and evaluation of their cytostatic activities are described. The mechanism of antiproliferative effect of 5-(2-chloroethyl)-substituted pyrimidine 3 that exerted the pronounced cytostatic activity was studied in further details on colon carcinoma (HCT116) cells. The cell cycle perturbation analysis demonstrated severe DNA damage (G2/M arrest) pointing to a potential DNA alkylating ability of 3. Preliminary ADME data of 3 and its 6-methylated structural congener (6-Me-3) showed their high permeability and good metabolic stability. © 2011 Elsevier Ltd. All rights reserved. Source

Hutinec A.,Galapagos Research Center Zagreb Ltd | Rupcic R.,Galapagos Research Center Zagreb Ltd | Caleta I.,Galapagos Research Center Zagreb Ltd | Orsulic M.,Galapagos Research Center Zagreb Ltd
Tetrahedron Letters | Year: 2011

The application of microwave heating to a polymer-assisted solution phase synthesis technique has been used to develop a rapid and efficient protocol for the solution phase synthesis of amides from unprotected polyfunctional 15-membered azalides. © 2010 Elsevier Ltd. All rights reserved. Source

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