Drug design and delivery最新文献

Both geometrical isomers (E and Z) of an aminotamoxifen (2) have been prepared as precursors of the corresponding E and Z iodotamoxifens (1). The ability of E and Z-1 and 2 to compete with [3H]estradiol for estrogen receptors in rat uterine cytosol was measured relative to Z-tamoxifen and estradiol. The four tamoxifen derivatives showed affinities ranging from 50% to 1600% of that of tamoxifen. Under the same conditions, tamoxifen's relative binding affinity was 0.2% of that of estradiol. Preparative routes to the radioiodo-tamoxifens, [131I]-E and Z-1, were also developed and provided approximately 100 MBq of 'no carrier added' material in 40-60% radiochemical yield. Study of the biodistribution of these radioligands in tumor-bearing mice demonstrated significant radioactivity in the tumors and in the uterus. For [131I]-E-1, target to background ratios reached 28 for uterus/blood and 10 for tumor/blood; corresponding optimum ratios for [131I]-Z-1 were 10 and 5. A washout study using estradiol indicated selective uptake in the uterus of Swiss white mice. However, tumor uptake and image contrast in humans following intravenous administration of either [131I]-E or Z-1 were insufficient to allow diagnostic use of the radioiodotamoxifens.

The evaluation of rosin, a rosin hard paraffin adduct, and four rosin esters as hydrophobic matrix materials for the controlled release of drugs is reported, using aspirin as a drug model. Aspirin matrix tablets were prepared using a wet granulation (nonaqueous) method, and were evaluated for various pharmaceutical parameters. Dissolution studies in pH 7.2 phosphate buffer showed that all formulations had hardness greater than 6 kg/cm2 and disintegration time greater than 150 min. Release of aspirin from the formulations obeyed a diffusion controlled first order kinetic and linear to the square root of time function. Two of the resin ester formulations had a T80% of more than 4 hr. The results suggest that these esters may find application in the development of sustained release formulations for the local treatment of dental diseases, or--as tablet matrices suitably coated with acid resistant material--in the development of oral sustained release drug delivery systems.

The percutaneous absorption promoting effect and skin irritancy of cyclic monoterpenes were investigated in rats and with rabbits, respectively. Ketoprofen (KPF) was applied to rat skin in gel ointments containing various cyclic monoterpenes. Plasma concentrations of KPF markedly increased with the addition of the hydrocarbons of cyclic monoterpenes such as trans-p-menthane and d-limonene, whereas no significant enhancing effect was observed in the cases of other terpenes such as l-menthol, l-menthone and 1,8-cineole. The lipophilicity of the enhancers seems the important factor in promoting penetration of KPF through the skin. The enhancing activity of d-limonene was found to be much higher than that of Azone. Irritancy of the hydrocarbons of cyclic monoterpenes and Azone to the skin was evaluated using a Draize scoring method with rabbits. No change was observed on the skin surface when ethanol containing 2% of the hydrocarbons was applied to the dorsal skin, though a slight edema and erythema were observed in the case of Azone. In particular, an obvious difference was observed in the erythema formation between Azone and the hydrocarbons of cyclic monoterpenes.

A series of 5-(pyridyl)-2H-tetrazol-2-acetic acids (16-21), esters (10-15), and amides (22-27) was synthesized in order to investigate the effect of 5-substituents (R1 = 2-, 3- or 4-pyridyl) and alpha-substituents (R2 = H, Me) on anti-inflammatory activity. The point of attachment of the R1-pyridyl substituent influenced potency. The relative potencies in the acetic acid ester, acetic acid and acetamide classes of compounds were 2- and 4- greater than 3-pyr, 2- and 3- greater than 4-pyr, and 4- greater than 2- and 3-pyr, respectively. In the acetic acid ester and acetamide classes, compounds having a R2 hydrogen substituent were generally more potent than corresponding methyl substituted compounds, whereas, in the acetic acid class the reverse applied. The relative order of anti-inflammatory potency was generally amide greater than ester greater than acid. 2-[5-(4-Pyridyl)-2H-tetrazol-2-yl]acetamide (26) was the most effective antiinflammatory agent in the series, reducing inflammation by 53% at 3 and 5 hr after a 25 mg/kg po dose.

3,5-Bis(benzylidene)-4-piperidones and related compounds were prepared and found to have between 100 and 9700 times the activity of N,N'-bis(2-chloroethyl)-N-nitrosourea towards P388 leukemia cells. The shapes of six of these molecules--determined by X-ray crystallography--were compared, but no correlation between the stereochemistry of the molecules or their electronic properties and cytotoxicity was apparent. Molecular modification of the compounds by forming two mono-benzylidene compounds, a related acyclic derivative and an N-acyl compound resulted in diminished but retained high cytotoxicity. Two representative compounds lowered glutathione levels of liver following their intraperitoneal injection into mice. Two quaternary ammonium compounds were shown to bind in the minor groove of DNA, while four related non-quaternary ammonium derivatives did not demonstrate this property. We conclude that the modes of action of these highly cytotoxic compounds include alkylation of cellular thiols and DNA binding, but interference with other biochemical processes is also probably involved.

Recombinant human interferon-gamma was conjugated with polyethylene glycol (PEG) using succinimidyl coupling of amino groups in the protein. The PEG conjugated material showed antiviral, growth inhibitory and macrophage activation activities indistinguishable from those of the unmodified protein. The PEG conjugation reduced the receptor binding affinity slightly, but increased the half-life of the protein when measured in rats. Almost no clearance was observed within 6 hr after injection for the PEG conjugated protein, whereas a rapid clearance was seen for the unmodified interferon-gamma. Two possible sites of PEG attachment were identified in the protein: the N-terminal amino group and either lysine 129 or 131.

The preparation of two 2-dialkylamino-1-oxa-2,3-dihydro-1H-phenalenes (3 and 4) is described. Lewis acid-catalyzed Baeyer-Villiger reaction of acenaphthenone (5) gave the lactone 6. Reduction afforded the lactol 7, which was reacted with amines to give the target compounds 3 and 4. Investigation of the effects of these compounds on catechol and indole metabolism revealed that they lack the dopamine antagonist or agonist and serotonin agonist properties of the respective deoxy analogues.

A novel cyclic peptide c(Arg-Pro-Asp-D-Val-Tyr) related to thymopentin--the immunostimulant pentapeptide contained in thymic hormones--was designed on the basis of theoretical computer modeling. We applied molecular dynamics/energy minimization techniques and restrained molecular dynamics to determine the preferred conformation of this peptide. The linear precursor of the peptide is biologically active and probably exists in a highly motile dynamical equilibrium of different conformations. Our calculations show that the cyclic peptide consists of a single conformational family containing a beta turn at position Pro 2. Experimental support for this conclusion was derived from 2-D NOE data in aqueous solution for the closely related analogue c(Arg-Lys-Glu-D-Val-Tyr). Synthesis and biological testing of the cyclic peptide is therefore indicated.

A new route has been developed for the preparation of 3'-N-protected doxorubicin analogues. 4-Demethoxy-3'-N-trifluoroacetyldoxorubicin (5) was synthesized in an approach to an orally active anthracycline analogue. Tested against the B-16 murine solid tumor in mice, this compound increased life span by 133% when it was administered intraperitoneally at 25 mg/kg, and by 52% when it was given orally at 50 mg/kg.

The skin permeation enhancement of papaverine hydrochloride by free fatty acids (C3-C12), monoglycerides (side chains C5-C12) and caprylic acid (C8) esters was evaluated using the excised hairless rat skin. Enhancement was marked in the case of glyceryl monocaprylate; the cumulative amount of papaverine that permeated through skin over 28 hours from an aqueous suspension was 29.7 mg/cm2 with, and 26.9 micrograms/cm2 without glyceryl monocaprylate. The mechanism of enhancement was studied by measuring the effect the enhancers had on the diffusion and partition parameters of papaverine. Free fatty acids mainly affected the drug's diffusion, and monoglycerides mainly affected the drug's partition. For monoglyceride enhancers, a good linear relationship between the flux of papaverine and the amount of enhancer in skin was established. n-Octanol-water partition coefficients (log Pcal) of the enhancers were selected as indicators of their physicochemical properties, and related to their penetration-enhancing abilities. A parabolic relationship was found between the log of the flux of papaverine and log Pcal, for all types of enhancers. The relationship may be a good indicator in predicting enhancing effects.