Erik Bramm

Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo

MC 903 is a novel vitamin D analogue which has been tested for its effects on cell differentiation and cell proliferation in vitro using the human histiocytic lymphoma cell line U937, and on calcium metabolism in rats in vivo. In the present investigation MC 903 was compared to the natural metabolite of vitamin D3, 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3] and to its synthetic analogue 1 alpha-hydroxycholecalciferol [1 alpha (OH)D3]. MC 903 was found to be a potent inducer of cell differentiation and to inhibit cell proliferation and DNA-synthesis in concentrations comparable to those observed with 1,25(OH)2D3. 1 alpha (OH)D3, which is only active after metabolic conversion to 1,25(OH)2D3, was more than 100 times less potent. Oral or intraperitoneal administration of MC 903 to rats showed that the compound was at least 100 times less active than 1,25(OH)2D3 and 1 alpha (OH)D3 in causing hypercalciuria, hypercalcemia and bone calcium mobilisation. The low vitamin D activity of MC 903 was further confirmed by administration of the compound to rachitic rats. The strong direct effects of MC 903 on cell proliferation and cell differentiation, coupled with its decreased activity as a classical vitamin D makes this compound an interesting candidate for studies in human proliferative disorders such as psoriasis.

Novel cyanoguanidines with potent oral antitumour activity

4-Pyridyl cyanoguanidines with hydrophobic aromatic side chains showed potent antiproliferative activity in the human breast and lung cancer cell lines MCF-7, NYH and H460. In vivo, treatment with N-(6-chlorophenoxyhexyl)-N′-cyano-N″-4-pyridylguanidine (18, 20 mg/kg/day po.), gave a complete remission of tumours in a model of NYH inoculated nude mice.

Effect of d-penicillamine in vitro and in vivo on macrophage phagocytosis

Abstract Preincubation of rat peritoneal macrophages with d -penicillamine increased their uptake of labelled aggregated human gamma globulin ([ 125 I]AHG) without affecting the rate of degradation of the aggregates. Administration of d -penicillamine (50 mg.kg −1 . day −1 p.o.) to normal rats resulted in increased uptake of [ 25 I]AHG by peritoneal macrophages after 4 days of treatment, but not after 14 and 28 days of treatment. In contrast, macrophages from rats with adjuvant arthritis treated with d -penicillamine (50 mg.kg −1 . day −1 p.o.) exhibited an increased uptake of [ 125 I]AHG throughout the course of the disease. Administration of d -penicillamine in vivo had no effect on the rate of degradation of [ 125 I]AHG by freshly prepared macrophages. Culture for 24 hr in vitro prior to incubation with [ 125 I]AHG led to a decrease in the rate of degradation of the labelled aggregates by macrophages from untreated or d -penicillamine-treated rats and from rats with adjuvant arthritis, but not by macrophages from d -penicillamine-treated adjuvant arthritic rats. It is suggested that d -penicillamine may exert a stimulatory effect on the reticuloendothelial function during chronic inflammatory disease, and that this effect may be mediated via an interaction with the macrophage plasma membrane.

Discovery of OT4003, a novel, potent, and orally active cys-LT1 receptor antagonist

The present paper describes the structural modifications leading to the discovery of a new series of quinoline-containing cys-LT1 receptor (LTD4 receptor) antagonists. A structural optimization with respect to the in vitro receptor binding, the in vivo brochoconstriction, and the toxicological effect in the form of peroxisomal proliferation was performed in order to achieve the target compound OT4003. OT4003 ((S)-(+)-E-2-(3-(2-(7- chloroquinolin-2-yl)ethenyl)phenylaminomethyl)-phenoxyl++ +-hexanoic acid) was found to be a potent and selective inhibitor of [3H]LTD4 specific binding to guinea pig lung membranes (IC50 2.4 +/- 1.0 nM), and also a potent, orally active, antagonist of LTD4 induced bronchoconstriction in guinea pigs [ED50 0.14 (ED16 0.1-ED84 0.4) mg/kg; 4 h pretreatment]. The enantiomerically pure OT4003 was prepared using a short convergent synthesis, including an enzymatic resolution step.

Actinomycin D Peritonitis in Rats

The injection of 50 μg i.p. of actinomycin D produces, in rats, a biphasic inflammatory reaction. The first short lasting phase (∼24 h) is characterized by the decrease of the peritoneal cells number,

Characterization of Inhibitor(s) of Lymphocyte Activation in Serum from Rats with Adjuvant Arthritis

Serum from adjuvant arthritic rats inhibits the concanavalin A- (Con A) and lipopolysaccharide-induced stimulation of lymph node cells, leaving the basal and phytohemagglutinin-stimulated 3H-thymidine incorporation unaffected. Con A-stimulated 3H-thymidine uptake is also inhibited in rat spleen and peripheral blood lymphocytes and in dog peripheral blood lymphocytes. The intensity of the inhibitory activity in serum is positively correlated with the intensity of the secondary lesions of adjuvant arthritis. Inhibitory activity was not found in serum from rats bearing nystatin-induced inflammation. Serum fractionation studies indicated that the inhibitory activity cannot be attributed to low molecular weight alpha2-glycoproteins or to gamma-globulins and alpha2-macroglobulins, but it is present in a fraction migrating with beta-globulins. The inhibitory activity in arthritic rat serum is reduced by treatment with non-steroidal anti-inflammatory drugs, but is unaltered by D-penicillamine. It is suggested that this inhibitory activity is part of the systemic response to an immunologically mediated inflammation.

Corrigendum to “Discovery of OT4003, a novel, potent and orally active Cys-LT1 receptor antagonist” (Bioorg. Med. Chem. 1997, 5, 415)

Department of Chemistry, Leo Pharmaceutical Products, Industriparken 55, DK-2750 Ballerup, Denmark Department of Biochemistry, Leo Pharmaceutical Products, Industriparken 55, DK-2750 Ballerup, Denmark Department of Pharmacology, Leo Pharmaceutical Products, Industriparken 55, DK-2750 Ballerup, Denmark Department of Toxicology, Leo Pharmaceutical Products, Industriparken 55, DK-2750 Ballerup, Denmark