New cyclooxygenase-2/5-lipoxygenase inhibitors. 3. 7-tert-butyl-2, 3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: variations at the 5 position.

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-buty1-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: discovery and variation of the 5-keto substituent.

A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible for the gastrointestinal safety of compounds such as 30.

Fluorescence decay kinetics of the tryptophyl residues of myoglobin: effect of heme ligation and evidence for discrete lifetime components.

The fluorescence decay kinetics of the tryptophyl residues of sperm whale and yellowfin tuna myoglobin have been determined by using time-correlated single photon counting, with picosecond resolution. Purification by HPLC techniques resulted in the isolation of samples that exclusively displayed picosecond decay kinetics. Lifetimes of 24.4 ps for Trp14 and 122.0 ps for Trp7 were found for oxy sperm whale myoglobin (pH 7), which agree with theoretical predictions [Hochstrasser, R. M., & Negus, D. K. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 4399-4403]. The effects of ligand binding and pH on the decay kinetics were investigated, and the results were shown to be consistent with the known crystal structures. Data for the met form of sperm whale myoglobin were analyzed both in terms of a sum of discrete exponential components and as a continuous gamma distribution of exponential decays. The results were not found to support the existence of multiple, structurally distinct conformation states in myoglobin.

Resolution of heterogeneous fluorescence into component decay-associated excitation spectra. Application to subtilisins.

Direct and indirect methods are described to combine steady-state and picosecond time-resolved fluorescence decay data to generate decay-associated excitation spectra. The heterogeneous fluorescence from a fluorophore mixture that models protein fluorescence was resolved into individual component excitation spectra. The two methods were also used to determine the excitation spectra associated with each of the decay time components for the proteins subtilisin Carlsberg and BPN'. On the basis of associated spectra, the decay components of both proteins were assigned to individual (or groups of) emitting species. The two approaches used to generate the decay-associated excitation spectra are compared and their general application to protein fluorescence studies is discussed.

Whole-body retention, excretion and metabolism of [74As]arsenic acid in the hamster.

In order to assess the whole-body retention, excretion and metabolism of inorganic arsenic, male and female hamsters were given either a single oral or i.v. dose of 74As (congruent to 33' microCi/hamster; 0.01 micrograms arsenic/hamster) as arsenic acid. 74As radioactivity was measured in the whole body, urine and feces for up to 35 days. 24-h samples of urine were analyzed for arsenic metabolites. For the i.v. dosed hamsters, the half-period of elimination for the first component (65% of the dose) was 0.40 days; the second component (35% of the dose) had a half-period of 4.5 days. For the orally dosed hamsters, the half-period of elimination for the first component (98% of the dose) was 0.29 days; the second component (2% of the dose) had a half-period of 3.8 days. Differences in the percent of dose excreted between oral and i.v. dosed hamsters appeared to be due to the increased fecal excretion of arsenic (70%) in the orally dosed hamsters as compared to the i.v.v dosed hamsters (6%). No statistically significant differences between the i.v. and oral treatments were found in the half-periods of elimination for either of the 2 components. Analysis of the urine for metabolites revealed arsenic was present as dimethylarsinic acid and inorganic arsenic.