Relative potencies of three glucocorticoids to induce hypoplasia of the physis and concomitant biochemical alterations in the rat.

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.

Macrolactonolides: a novel class of anti-inflammatory compounds.

A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17ß-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.

Synthesis, biological activity and molecular modeling studies of novel COX-1 inhibitors.

Synthesis of new potential COX-1 and/or COX-2 inhibitors, derivatives of 1,1-di-(3-carboxyphenyl)ethane, their biological activity, docking results on COX-1 enzyme and absorption, distribution, metabolism, excretion (ADME) properties are presented. In addition to known interactions between ketoprofen and ibuprofen, leading NSAID agents and COX-1 active site, the possibility of formation of additional interactions is explored. Interactions with Ala527, and with one of the water molecules situated within the active site are identified. Molecular mechanics and DFT calculations for studied compounds have revealed free rotation around two central bonds (C1-C3' and C1-C3"), making them flexible, thus easier to enter and adjust to the active site. Further modifications of core structure have been undertaken to optimize biological activity and ADME properties. As a result, two of the compounds are indicated as novel COX-1 inhibitors.