Biphenylcarboxamide derivatives as antagonists of platelet-activating factor.

A series of N-[4-(3-pyridinyl)butyl]-1,1'-biphenyl-4-carboxamides was prepared, and the compounds were evaluated for platelet-activating factor (PAF) antagonist activity in a binding assay employing washed, whole dog platelets and in vivo for their ability to inhibit PAF-induced bronchoconstriction in the guinea pig. The inclusion of a methyl group in the R configuration on the side-chain carbon adjacent to the carboxamide nitrogen atom of these derivatives resulted in a marked enhancement of potency in the binding assay for compounds unsubstituted in the biphenyl 2-position and, more importantly, in improved oral bioavailability. Previous work with related pyrido[2,1-b]-quinazoline-8-carboxamides suggests that the presence of such an alkyl group improves bioavailability by rendering the resulting compounds resistant to degradation by liver amidases. The most interesting compounds to emerge from this work are (R)-2-bromo-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]-1,1'-bi phe nyl- 4-carboxamide (33) and (R)-2-butyl-3',4'-dimethoxy-N-[1-methyl-4-(3-pyridinyl)butyl]- 1,1'-biphenyl-4-carboxamide (40) each of which inhibits PAF-induced bronchoconstriction in the guinea pig by greater than 55%. 6 h after an oral dose of 50 mg/kg.

Pentadienyl carboxamide derivatives as antagonists of platelet-activating factor.

A series of N-[4-(3-pyridinyl)butyl]-5,5-disubstituted-pentadienamides was prepared and evaluated for PAF-antagonist activity. Compounds were assayed in vitro in a PAF-binding assay employing washed, whole dog platelets as the receptor source and in vivo after intravenous or oral administration for their ability to prevent PAF-induced bronchoconstriction in guinea pigs. Criteria required for good oral activity in the latter model include an (E,-E)-5-phenyl-2,4-pentadienamide, a second phenyl or a four- or five-carbon alkyl moiety in the 5-position of the diene, and an (R)-[1-alkyl-4-(3-pyridinyl)butyl] substituent on the carboxamide nitrogen atom. The alkyl substituent on this side chain can be methyl, ethyl, or cyclopropyl. Two members of this series, [R-(E)]-5,5-bis(4-methoxy-phenyl)-N- [1-methyl-4-(3-pyridinyl)butyl]- 2,4-pentadienamide (31) and [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4- (3-pyridinyl)butyl]-2,4-decadienamide (58), were selected for further pharmacological evaluation. Both were found to be substantially longer acting after oral administration than the corresponding S enantiomers in the guinea pig bronchoconstriction assay. A second in vivo model used to evaluate PAF antagonists determines the ability of test compounds to decrease the area of skin wheals induced by an intradermal injection of PAF. In this model, using both rats and guinea pigs, compounds 31 and 58 were found to be as active as the reference PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H- 1-(4-morpholinyl)-1-propanone (45).

Reflex sympathetic dystrophy: an underreported syndrome in children?

Two cases of reflex sympathetic dystrophy are described in a 13-year-old and a 10-year-old girl. In the latter, symptoms occurred consecutively in the right leg, the left foot and the left hand. In contrast to the usual findings in adults, bone scintigraphy showed decreased radio-isotope uptake in the affected area during the early phase. An electromyography performed in the younger patient showed slower nerve conduction velocity in the affected limb. The younger girl improved following physical therapy and calcitonin injections, while the older patient favorably responded to sympathetic blockade.

Substituted (aryloxy)alkanoic acids as antagonists of slow-reacting substance of anaphylaxis.

A series of compounds in which the 4-acetyl-3-hydroxy-2-propylphenoxy moiety of the standard SRS-A antagonist, FPL-55712, is linked by a polymethylene or a polyether chain to substituted (aryloxy)alkanoic acids was prepared. The compounds were evaluated for their ability to antagonize SRS-A-induced contractions of guinea pig ilea and LTE-induced bronchoconstriction in the guinea pig. The results showed that the compounds were all less potent than FPL-55712 in vitro, yet surprisingly, most were more potent by the inhalation route of administration. Some of the most potent analogues were selected for further pharmacological evaluation and, by inhalation, exhibited selective antagonism of leukotrienes as compared with PAF or histamine. In comparison to FPL-55712, compounds 28 and 37 were more potent against LTE (40- and 80-fold, respectively), LTD (4- and 3-fold, respectively), and LTC (27- and 20-fold, respectively) induced bronchoconstriction when tested by inhalation.

(E)-3-(4-Oxo-4H-quinazolin-3-yl)-2-propenoic acids, a new series of antiallergy agents.

A series of substituted (E)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenoic acids was prepared and evaluated in the rat passive cutaneous anaphylaxis (PCA) test for antiallergic activity. Alkoxy, alkylthio, and isopropyl substituents at the 6- or 8-positions provided highly potent compounds. Conversion to the Z isomer, reduction of the side chain double bond, or reduction of the quinazoline ring resulted in substantial loss of activity. Among the analogues that exhibited oral activity in the PCA test, (E)-3-[6-(methylthio)-4-oxo-4H-quinazolin-3-yl]-2-propenoic acid (5i) was the most potent.

Pyrido[2,1-b]quinazolinecarboxylic acids as orally active antiallergy agents.

A series of 8-substituted pyrido[2,1-]quinazoline-2-carboxylic acids was prepared by the nickel carbonyl mediated carboxylation of the corresponding bromides. The activities of these compounds in the rat PCA test are comparable to those of the corresponding 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids.

Fluorescent assay for estimating the binding of erythromycin derivatives to ribosomes.

A fluorescent erythromycin derivative was used to determine the binding of erythromycin derivatives to ribosomes. The assay is rapid, sensitive, and convenient. Because measurements are made in solution, they represent equilibrium conditions, unlike filter binding assays which perturb the equilibrium. Results correlate well with measurements made by other techniques.

A new semisynthetic macrolide antibiotic 3-O-oleandrosyl-5-O-desosaminylerythronolide A oxime.

A new antibiotic, 3-O-oleandrosyl-5-O-desosaminylerythronolide A oxime (3) was produced from erythronolide A oxime (1) by the oleandomycin-producing culture, Streptomyces antibioticus ATCC 11891. The structure of 3 was determined by degradative studies and confirmed by X-ray analysis. Compound 3 was found to be less active, but more stable to acid, then erythromycin A oxime.

Induction of erythromycin resistance in Staphyloccus aureus by erythromycin derivatives.

The ability of 53 erythromycin analogues to induce resistance to erythromycin in Staphlococcus aureus was evaluated. Only derivatives with antibacterial activity induced resistance, although some antibacterial compounds did not induce resistance. No derivatives without antibacterial activity but with ability to induce resistance were found.

Aromatic esters of 5-O-desosaminylerythronolide A oxime.

Several substituted aromatic esters of the C-3 hydroxyl of 5-O-desosaminylerythronolide A oxime were prepared. Ribosomal binding studies showed that meta substituents on the aromatic ring gave the most active analogs. The esters described were all inactive in vivo at the maximum level tested.

Effect of erythromycin analogues on binding of [14C]erythromycin to Escherichia coli ribosomes.

The relative ability of 44 erythromycin analogues to bind to ribosomes was determined by their effect on [(14)C]erythromycin binding to Escherichia coli ribosomes. The association and dissociation constants of each of these erythromycin derivatives were determined as well as their interaction coefficient for their binding to ribosomes. Substitutions were made on various portions of the erythromycin molecule with retention of substantial activity as measured by inhibition of [(14)C]erythromycin binding to ribosomes. Since the effect of erythromycin analogues on [(14)C]erythromycin binding to ribosomes provides a relatively sensitive assay for these compounds, erythromycin analogues with relatively little affinity for ribosomes could be detected. Compounds with association constants of 10(4) M(-1) were detectable; the association constant for erythromycin binding to ribosomes was approximately 10(8) M(-1). Thus, compounds with 0.0001 the association constant of erythromycin were detectable. This assay could be used alone or in conjunction with microbiological assays for primary screening of active analogues or other compounds which interfere with [(14)C]erythromycin binding to ribosomes. It permits an estimate of the general activity of compounds rapidly and directly. Variables such as metabolic modifications of the compounds and permeability are excluded. The present assay reflects the ability of the compounds to interact directly with their target organelle and may serve as a useful adjunct in developing new compounds.

Correlation of effects of erythromycin analogues on intact bacteria and on [14C]erythromycin binding to Escherichia coli ribosomes.

The dissociation constants for binding to ribosomes from Escherichia coli and concentrations at which 50% inhibition of [(14)C]erythromycin binding to ribosomes occurred were determined for 45 erythromycin analogues. These values were correlated with their antibacterial activities against Bacillus subtilis. Compounds which bound to ribosomes best showed the greatest activities; those which were poorly bound to ribosomes showed little or no antibacterial activity. The ribosomal binding assays therefore reflected the general antibacterial potential of the erythromycin analogues.

Inhibition of [14C]chloramphenicol binding to Escherichia coli ribosomes by erythromycin derivatives.

The effect of erythromycin A and 35 analogues of erythromycin A on [(14)C]chloramphenicol binding to Escherichia coli ribosomes was evaluated. Substitutions on various portions of the erythromycin molecule were made with retention of ability to bind to ribosomes. Specifically, substantial activity in interference with [(14)C]chloramphenicol binding was retained upon removal of the cladinose and various substitutions on the 3-hydroxyl, the oxime, and 2-hydroxyl groups. Erythromycin analogues with relatively poor binding activity to ribosomes could be detected. This assay can be used alone or in conjunction with microbiological assays for screening of active analogues. It permits an estimate of the general binding activity of compounds rapidly and directly. The assay reflects the ability of the compounds to interact with their target organelle, the ribosome, and may serve as a useful adjunct in developing new compounds.