Biomedical subjects

Klaus Rehse

Publications and source records attributed to Klaus Rehse.

7 recordsLinked to original sources

PubMed2006

New purines with antiplatelet activity.

Four purine-2,6-diamines, 4a, b, 5a, b, nineteen N-(purin-2-yl)benzenecarboxamides 6a-q, 7b, and one N-(purin-2-yl)-2-furanecarboxamide 8 were prepared for the first time and tested for their inhibition of blood platelet aggregation. Six compounds, 6a, b, h, m, o, p, inhibited the platelet aggregation induced by collagen with IC(50 )values between 3 and 10 micromol/L in the Born test. ADP, PAF, and adrenaline were used as specific aggregation inducers to examine the mechanism of the anti-aggregating activity. An astonishing pattern of activities in the nanomolar, with 6m, 7b, 8 and even subnanomolar range, with 6b, was observed. Compound 6b inhibited the platelet aggregation induced by ADP with an IC(50) = 0.45 nM (6m: 3.5 nM; 8: 30 nM). Compound 7b showed an antagonism against the inducer adrenaline with an IC(50) = 1.8 nM (6o: 20 nM; 8: 30 nM). The strongest antagonism against PAF was observed with 7b showing an IC(50) = 1 nM (6b: 35 nM; 8: 74 nM).

Epinephrine↗

PubMed2005

New oxadiazole derivatives showing partly antiplatelet, antithrombotic and serotonin antagonistic properties.

Ten new 1, 2, 4-oxadiazole- and six new 1, 3, 4-oxadiazole-carboxamides containing different lipophilic moieties (i.e. 4-biphenyl-, 1-naphthyl, phenylpropyl- and n-hexyl substituents) and additional basic groups which are mainly alkyl- and dialkylaminoalkyl residues have been synthesized and tested for antiplatelet effects in vitro (Born-test) and antithrombotic properties in vivo (laser thrombosis model). If the platelet aggregation was induced by collagen, the inhibitory effects (IC50) were between 58 microM and 300 microM. Using serotonin (5-HT) as an inducer, compound 6a (N-(3-dimethylaminopropyl-5-(biphenyl-4-yl)-1, 3, 4-oxadiazole-2-carboxamide) had an IC50 = 1 microM (12e: (N-3-Dimethylaminopropyl)-3-(1-naphthyl)-1, 2, 4-oxadiazole-5-carboxamide, 6.7 microM). In an in vitro rat tail artery assay 6a and 12e behaved as a competitive 5-HT2A receptor antagonist (6a: pKB = 6.86 +/- 0.04; 12e: pKB = 6.66 +/- 0.05). The antithrombotic effects of some compounds were small but significant (7-10 % inhibition of thrombus formation).

Fibrinolytic Agents↗

PubMed2005

Synthesis and antiplatelet activity of new imidazole-4-carboxylic acid derivatives.

1-Arylalkyl-5-phenylsulfonamino-imidazole-4-carboxylic acid esters and their carboxamides with an additional secondary amino group were synthesized and identified as antiplatelet agents in a low micromolar range (Born-test, inducer collagen). To describe the mechanism of action more precisely the Born-test was carried out as well with ADP, adrenaline or PAF, respectively. In addition, two compounds were investigated for their COX-1 inhibitory activities. Provided the essential structural criteria are met i.e. amide group or ester, sulfonylamino rest, hydrophobic moieties, and a secondary amino function, slight structural modifications are able to shift the pattern of activity among the above platelet receptors. So, the ester 5c exhibits PAF antagonistic activity at IC(50) = 1 microM and COX-1 inhibition (IC(50) = 0.4 microM). The carboxamide 6c shows ADP antagonistic properties (IC(50) = 2 microM). Compound 6g is as well PAF antagonistic (IC(50) = 4 microM) and a COX-1 inhibitor (IC(50) = 1 microM). The derivative 6i shows a strong antiadrenergic (IC(50) = 0.15 microM) and PAF antagonistic (IC(50) = 0.66 microM) effect.

Animals↗

PubMed2005

New pyrimido[5,4-c]cinnolines with antiplatelet activities.

Twenty one new pyrimido[5,4-c]cinnolines containing different lipophilic moieties (viz. phenyl, 4-methoxyphenyl, 2-furanyl, 2-thienyl) in position 2 and additional basic groups (e.g., alkylaminopropyl, dialkylaminopropyl and cyclohexylaminopropyl) in position 4 of the title ring system have been prepared and investigated for antiplatelet effects (Born test). Ten of them inhibited the platelet aggregation induced by collagen with an IC(50) below 10 micromol/L (6a, 6b, 6c, 6g, 6h, 6i, 6k, 6m, 6q, 6u). A closer inspection of the antiplatelet effect with other inducers showed antagonism against adrenaline (6m), ADP antagonist (6i) and PAF antagonist activities (6m, 6i, 6u) in nanomolar (IC(50)) concentration ranges.

Blood Platelets↗

PubMed2004

New antithrombotics with an indazole structure.

Fifteen new indazole derivatives have been synthesized. In the Born test, compounds (4f) and (4g) were most active. They inhibited the blood platelet aggregation induced by collagen with an IC(50) = 85 or 90 microM, respectively. After oral administration to rats (60 mg/kg) three of the compounds significantly inhibited the formation of thrombi in arterioles and venules. The strongest effect was observed with (4j) which showed an inhibition of 15% in arterioles and 7% in venules. Further experiments showed that compound (4j) does not mediate these effects by activating soluble guanylate cyclase, but likely by inhibiting phosphodiesterase isoform PDE 5.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2004

Antiaggregating and antithrombotic activities of new 1, 2, 3-triazolecarboxamides.

Twenty five new triazolecarboxamides related to YC-1 were prepared and tested for their antiplatelet (in vitro) and antithrombotic (in vivo) activities. Five of them inhibited the aggregation of blood platelets (Born test, inducer collagen) with IC50 values between 90 and 130 microM. Nine compounds exhibited significant antithrombotic properties with an inhibition of thrombus formation between 11 and 7%. Only one compound (8c) showed both, in vitro and in vivo effects. In vitro, the most active compounds were 11c and 12d. They inhibit platelet aggregation with IC50 = 90 and 95 microM. In vivo, 10a showed the strongest inhibition of thrombus formation with 11% in arterioles (5% in venules) after a single oral dose of 60 mg/kg. With serotonin as inducer both, 11c and 12d, showed lower IC50 values namely 25 or 30 microM, respectively. Additional antiplatelet activities were found for 11c against adrenaline (IC50 = 25 microM) and for 12d against platelet activating factor (PAF) (IC50 = 15 microM) as inducer.

Animals↗

PubMed2003

New antithrombotic 1-phthalazinamines with serotonin antagonistic properties.

We report nineteen 4-aryl- and 4-arylalkyl-1-phthalazinamines (5-8) which we prepared and tested for antithrombotic properties. All compounds were assayed for their antiplatelet activity in the "Born test" with collagen as inducer of the aggregation. N-[4-(1H-1, 2, 4-triazol-1-yl)butyl]-4-phenyl-1-phthalazin-amine (7 c) was the most potent compound, having an IC(50) of 8 microM. When 5-HT (Serotonin) was used to start aggregation the N-(furan-2-yl-methyl)-4-phenyl-1-pthtalazinamine (8 a) had an IC(50) of 2 microM. In vivo potencies were highly significant. N-[5-(1H-1, 2, 4-triazol-1-yl)pentyl]-4-phenyl-1-phthalazinamine (7 d) inhibited thrombus formation by 12% (P < 0.002) in arterioles and 7% (P < 0.01) in venoles as tested with our laser thrombosis model. For compound 8 a we surprisingly found an antagonism to the 5HT(2A) receptor, which is most likely the mechanism of the inhibition of aggregation by this compound.

Administration, Oral↗