ABSTRACT
The synthesis and SAR development of a trisubstituted imidazole HDAC inhibitor is described. The compounds were synthesized with high diastereocontrol by leveraging Ellman sulfinyl imine chemistry. Structural elucidation provided insight into binding mode and supported design rational. Pharmacokinetic properties of lead compounds were determined.
Subject(s)
Histone Deacetylase Inhibitors/metabolism , Histone Deacetylases/metabolism , Animals , CD4-Positive T-Lymphocytes/virology , Crystallography, X-Ray , HIV-1/drug effects , HIV-1/physiology , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/chemistry , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/pharmacology , Inhibitory Concentration 50 , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.
Subject(s)
Anti-HIV Agents/pharmacology , HIV-1/drug effects , Histone Deacetylase Inhibitors/pharmacology , Ketones/pharmacology , Virus Activation/drug effects , Virus Latency/drug effects , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line, Tumor , Dogs , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacokinetics , Humans , Ketones/chemical synthesis , Ketones/pharmacokinetics , Microbial Sensitivity Tests , Rats , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacologyABSTRACT
The aim of this study was to design a simple field test to measure the anaerobic endurance fitness of rugby league players, which is an important fitness quality in the game of rugby league. Twelve amateur football players with a mean (+/-SD) age of 21.5 years (+/-2.2) volunteered to participate in the study. The subjects completed 1 trial of the Wingate 60-second (W60) cycle test and 2 trials of the new Triple-120 meter shuttle (T120S) test. All trials were completed 4 days apart. The validity of the T120S was determined by comparing physiological responses (heart rate and blood lactate) and rating of perceived exertion to the all-out W60 cycle test. The results indicate there is a significant relationship between maximum heart rate (r = 0.63 and 0.71) for the 2 trials of the T120S and the W60 cycle test. There was no significant relationship between the 2 trials and the W60 cycle test for post 3 minute lactate (r = 0.112 and 0.101) and rating of perceived exertion (r = 0.94 and 0.161). However, the T120S test elicited greater mean values for these measures than the W60 cycle test. The results indicate that the T120S is a valid test of anaerobic endurance and represents a sports specific test of this quality that may provide useful information for players and coaches involved in the sport of rugby league.
Subject(s)
Anaerobic Threshold/physiology , Exercise Test/methods , Football/physiology , Physical Endurance/physiology , Physical Fitness/physiology , Adult , Heart Rate/physiology , Humans , Lactic Acid/blood , Male , Reproducibility of ResultsABSTRACT
Body mass changes, hematocrit, specific gravity and urine colour were recorded during two games of soccer to determine which of these methods was the most practical in a field setting for monitoring dehydration. Members (n=13) of a premiership soccer team with a mean age of 22.6 (+/-4.9) years old, height of 177.8 (+/-7.1)cm and sum of skinfolds (four sites) of 37 (+/-12.8) were invited to participate in this study with 11 participating in each game. Players had weight, hematocrit, specific gravity and urine colour recorded pre- and post-game. Players were allowed to ingest fluid ad libitum throughout the matches with the amount consumed recorded. Urine excretion was also recorded and included in the calculation of final body mass loss (kg). A mean ambient temperature of 21 degrees C and relative humidity 77% was recorded for both games. Pre- and post-game body mass, sweat loss, hematocrit, urine specific gravity and colour were significantly different (p<0.01) for both games. Linear mixed effects models were fitted to the data in order to identify an optimal prediction equation for sweat loss. The model predicting from mass change was clearly the best fitting. The results demonstrate that a change in body mass during a game of soccer is an effective method of monitoring dehydration due to sweat loss when compared to other known methods that may be invasive and inappropriate in the field.
