New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents.

A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 microM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 microM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 microM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin-induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 microM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.

Alveolar lavage cytology in transplanted lungs. I. Staining methods and findings in dogs with autografts and allografts without immunosuppression.

Alveolar lavages were performed repetitively on the normal and transplanted lungs of dogs that had recieved autografts or allografts without immunosuppression. One half of the lavage returns was fixed as a cytologic smear; the other half was subjected to semi-thin section or electron microscopic examination. Of the staining methods was used, the periodic acid-Schiff (PAS) and Giemsa techniques were best for differentiating and counting cells. The Ladewig technique was best for evaluating the presence and location of fibrin. After autotransplantation, the proportion of so-called alveolar marcophages increased, reached a peak in 4 to 7 days, and then returned to normal. Phagocytized fibrin increased for the first postoperative week, but not extracellular fibrin was ever observed. After allotransplantation, a progressive decrease in the proportion, size, and vacuolization of so-called alveolar macrophages was noted along with an increase in extracellular fibrin. Intracellular fibrin could be detected only up to the third day. These findings define adequate methods for preparing and staining material obtained from diagnostic alveolar lavages, and they suggest that the procedure may serve as an index of lung allograft rejection.