Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.     

Electrochemical assay for deoxyribonuclease I activity

A thiolated oligonucleotide having three ferrocenes was immobilized on a gold electrode through the sulfur-gold linkage. This electrode showed a current response based on the redox reaction of the ferrocene moieties and this response was decreased after treatment with deoxyribonuclease I (DNase I), suggesting the disappearance of the ferrocene moieties on the electrode by the DNase I digestion. A linear correlation between i₀ and i, which are current peaks before and after DNase I treatment, respectively, was observed and this slope was decreased with increase in the amount of DNase I. No current decrease was observed in the presence of EDTA or RNase A instead of DNase I. These results suggested that the current decrease responded specifically to the amount of DNase I and this electrode could be used for an electrochemical DNase I assay. Under the optimum conditions of DNase I digestion at 37 °C for 30 min, a quantitative analysis could be achieved in the range of 10⁻⁴-10⁻² units/μl of DNase I.     

Protein requirement of the prawn Marsupenaeus japonicus estimated by a factorial method

The protein requirement to give maximum body protein retention in the prawn Marsupenaeus japonicus was assessed by determining both daily protein needed for maintenance (M) and daily body protein increment (G) when the juvenile prawn was maintained on a diet containing high quality protein. The body protein increment was obtained by determining carcass nitrogen increment when the prawn was fed on casein-based diets. The protein required for maintenance was estimated by regressing weight gains of the prawn on the diets containing graded levels of casein. True daily increase or retention of body protein in the prawn corresponded to the sum of G and M, and it was 3.2 g protein per kg body weight per day. The dietary protein requirement of juvenile M. japonicus for maximum body protein retention was suggested to be about 10 g per kg body weight per day providing that the prawn was fed the casein-based diet containing 50% crude protein (net protein utilization = 32) at the feeding level of 2%.     

Fundal height as a predictor of early preterm triplet delivery.

The purpose of this study was to create graphs of fundal height parameters in triplet pregnancies compared with those in twin pregnancies, and to investigate whether larger fundal heights in triplet pregnancies would predispose them to earlier delivery (before 34 weeks). The subjects were 727 twin pregnant women and 133 triplet pregnant women, who delivered after 1984. Triplet pregnancies showed significantly higher fundal heights compared with twin pregnancies at each gestational age (weeks). In triplet pregnancies, a single fundal height measurement above the 90th percentile before 34 weeks yielded a sensitivity of 31.3% and specificity of 82.4% for delivery before 34 weeks, with a positive predictive value of 50.0% and a negative predictive value of 68.0%. After adjusting for each associated factor using logistic regression, the risk of preterm labour was not significantly associated with a single fundal height measurement above the 90th percentile recorded before 34 weeks.     

Seasonal Changes in Nitrogen Fractions of Coptis japonica, a Temperate Forest Evergreen Chamaephyte, and their Ecological Implications

Seasonal changes in several forms of nitrogen were investigatedin Coptis japonica, an evergreen rosette hemicryptophyte intemperate deciduous forest. The concentration of total nitrogenin rhizomes and roots decreased during the period of new shootgrowth from winter to spring. In the rhizomes, total solubleprotein stored by early summer decreased gradually until winter,coupled with an increase in free amino acids. Nitrogen was largelystored in free amino acids in the roots, especially during summer.The total soluble protein in current-year leaves decreased fromspring to summer and then increased during winter. The seasonalchanges in nitrogen components were coincident with the changein light-saturated photosynthetic rates recorded in a previousstudy. The ratio of total soluble protein to total nitrogendecreased from spring to summer and then increased from latesummer to winter in the current-year leaves. In contrast, chlorophyllcontent and the ratio of chlorophyll to total nitrogen werehigher in summer than in other seasons. The results indicatethat nitrogen was used in a manner that better utilizes thevery weak light in summer and the higher light intensities inother seasons. The major component of the free amino acid poolwas asparagine, in every organ throughout the season, exceptfor the senescent leaves. Since asparagine has a high N:C ratio,we suppose that the asparagine-dominated amino acid pool isadvantageous in the carbon-limited environment of the forestfloor.Copyright 1994, 1999 Academic Press Free amino acid composition, total nitrogen, total soluble protein, photosynthesis, evergreen hemicryptophyte     

Transient Changes in the Energy State of Adenylates and the Redox States of Pyridine Nucleotides in Chlorella Cells Induced by Environmental Changes

The unicellular green algae Chlorella ellipsoidea was used tostudy transient changes in the energy state of adenylates andthe redox states of pyridine nucleotides induced by environmentalchanges. The transition from anaerobic to aerobic conditionsin the dark induced a sharp rise in the ATP ratio [ATP/(ATP+ADP+AMP)],a sudden decrease in the NADH ratio [NADH/(NAD⁺+NADPH)] anda transient drop in the NADPH ratio [NADPH/(NADP⁺+NADPH)]. Illuminationafter a dark period under anaerobic, CO₂-free conditions inducedsharp increases in the ATP and NADPH ratios and a slower decreasein the NADH ratio. Illumination under aerobic conditions, ineither the presence or absence of CO₂, caused a sharp increasein the NADPH ratio, a small increase in the ATP ratio and aslower increase in the NADH ratio. In the presence of CO₂, asubsequent large drop in the NADPH ratio occurred. Darkeningunder anaerobic, CO₂-free conditions induced a sudden decreasein the ATP ratio, a temporary fall in the NADPH ratio and aslow increase in the NADH ratio. Darkening under aerobic conditionsinduced transient drops in the ATP and NADPH ratios and a suddendrop in the NADH ratio. The addition of CO₂ to the atmospherewith illumination produced a decrease in all three parameters. These results are discussed in relation to current theoriesof the interaction between photosynthesis and respiration. Ourobservations indicate that the energy and reducing potentialsgenerated by photochemical processes are used for and controlother processes besides CO₂ fixation in photosynthetic cells. (Received December 3, 1981; Accepted May 4, 1982)