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PubMed2000

New carbamoylpiperidines as human platelet aggregation inhibitors.

A series of 3-carbamoylpiperidines (nipecotamides) are designed, synthesized and tested for their inhibitory action against adenosine diphosphate (ADP)-induced aggregation of human platelets. A structure-activity analysis of the bis(nipecotamido)aralkane type showed that a substituent on the piperidine ring should preferably be an amide and that the electronegativity of the carbonyl oxygen and the orientation of the amide group affected activities. Based on the knowledge of factors influencing platelet activation and aggregation, a nitric ester moiety which could release nitric oxide (NO) in situ, is incorporated into the nipecotamide structure. These compounds exhibit increased activity compared to those having no -ONO2 function. They also show stereoselectivity, with the meso isomer being approximately twice as potent as the synthetic diastereomeric mixture. Replacement of the -ONO2 function with hydroxyl, ester or alkyl groups considerably diminishes aggregation-inhibitory potential. Nipecotamides are shown here to inhibit the basal and collagen-induced rise in platelet inositol trisphosphate (IP3) levels, as well as phosphoinositide turnover. A comprehensive mechanism of action is proposed taking earlier results into consideration.

Adult↗
PubMed2004

Crystal structure of an acidic platelet aggregation inhibitor and hypotensive phospholipase A2 in the monomeric and dimeric states: insights into its oligomeric state.

Phospholipases A2 belong to the superfamily of proteins which hydrolyzes the sn-2 acyl groups of membrane phospholipids to release arachidonic acid and lysophospholipids. An acidic phospholipase A2 isolated from Bothrops jararacussu snake venom presents a high catalytic, platelet aggregation inhibition and hypotensive activities. This protein was crystallized in two oligomeric states: monomeric and dimeric. The crystal structures were solved at 1.79 and 1.90 angstroms resolution, respectively, for the two states. It was identified a Na+ ion at the center of Ca2+-binding site of the monomeric form. A novel dimeric conformation with the active sites exposed to the solvent was observed. Conformational states of the molecule may be due to the physicochemical conditions used in the crystallization experiments. We suggest dimeric state is one found in vivo.

Amino Acid Sequence↗
PubMed2002

Human platelet aggregation inhibitors from thyme (Thymus vulgaris L.).

Two antiaggregant compounds, thymol (compound 1) and 3,4,3',4'-tetrahydroxy-5,5'-diisopropyl-2,2'-dimethylbiphenyl (compound 2) were isolated from the leaves of thyme (Thymus vulgaris L.). The structures were determined by (1)H-, (13)C-NMR and mass spectra (MS) studies. These compounds inhibited platelet aggregation induced by collagen, ADP, arachidonic acid (AA) and thrombin except that compound 2 did not inhibit platelet aggregation induced by thrombin.

Humans↗
PubMed1996

A platelet aggregation inhibitor phospholipase A2 from Russell's viper (Vipera russelli) venom: isolation and characterization.

Vipera russelli venom is reported to contain multiple forms of phospholipase A2 (PLA2). Three PLA2s (VRV-PL-V, VRV-PL-VI and VRV-PL-VIIIa) have been purified and characterized in this laboratory. A PLA2(VRV-PL-IIIb) inhibiting platelet aggregation was purified from the same venom in two steps involving CM-Sephadex C-25 column chromatography followed by gel filtration on Sephadex G-50. VRV-PL-IIIb is a basic (pI 7.3-7.7) isoenzyme, with a mol. wt between 14,000 and 15,000. It induced neurotoxic symptoms in experimental mice with an i.p. LD50 of 5.2 mg/kg body weight. VRV-PL-IIIb inhibits ADP-induced platelet aggregation in a dose-dependent manner. It induced oedema in the foot pads of mice and is devoid of anticoagulant, myotoxic and direct haemolytic activities. Antibodies to VRV-PL-IIIb showed a single precipitin line against the antigen as well as whole venom.

Animals↗
PubMedDate not supplied

Synthesis of 6-[(4-imidazol-1-yl)-phenyl]-4-phenyl 4,5-dihydro-2H-pyridazin-3-one: a potential blood platelet aggregation inhibitor.

A new 4,5 diaryl pyridazin-3-one, an analogue of imazodan and Cl-930 was prepared starting from conveniently available chalcone. The resulting derivative was tested in order to determine the area of pharmacological activity. This compound was devoid of positive inotropic effects but showed an important inhibition of PAF-acether induced blood platelet aggregation in vitro with a Cl50 value of 3,4 microM. Ex vivo, anti-aggregating effect against PAF-acether was less important with a DE50 value of 63 mg/kg per os.

Animals↗
PubMed1990

Platelet aggregation inhibitors in hot water extract of green tea.

The effect of hot water extract of green tea on the collagen-induced aggregation of washed rabbit platelets was examined. The extract lowered submaximal aggregation and prolonged the lag time in a dose-dependent manner. After fractionation of the extract, it was revealed that the tea catechins (tannins) are active principles for inhibition and that ester-type catechins are more effective than free-type catechins. One of the ester type catechins, epigallocatechin gallate (EGCG), suppressed the collagen-induced platelet aggregation completely at the concentration of 0.2 mg/ml (= 0.45 mM). Comparing IC50 values of EGCG and aspirin it was found that the potency of EGCG is comparable to that of aspirin. Thrombin- and platelet activating factor (PAF)-induced aggregation was also inhibited by EGCG. The elevation of cyclic adenosine 3',5'-monophosphate (cAMP) level was not observed in EGCG treated platelets.

Animals↗
PubMed2003

Neuroprotective effect of SolCD39, a novel platelet aggregation inhibitor, on transient middle cerebral artery occlusion in rats.

BACKGROUND AND PURPOSE: SolCD39 is a soluble form of recombinant human ecto-ATP/ADPase (NTPDase1) and represents a new class of antithrombotic agents. SolCD39 blocks and reverses platelet activation, preventing recruitment of additional platelets into a growing thrombus. The purpose of this study was to examine the effect of solCD39 on neurological deficit, infarct size, and extent of edema after transient middle cerebral artery occlusion (MCAO) in rats. METHODS: Physiologically controlled Sprague-Dawley rats underwent 2-hour MCAO by retrograde insertion of an intraluminal suture coated with poly-l-lysine. The agent (solCD39) was administered intravenously before MCAO or at 1-hour or 3-hour recirculation. Other groups received vehicle (Tris-buffered saline) or human albumin (as a "positive" neuroprotective control; 25%, 0.5% of body weight) at 1-hour recirculation. Neurological status was evaluated during occlusion (at 60 minutes) and daily for 3 days after MCAO. Brains were perfusion-fixed at 72 hours, and infarct volumes and brain swelling were determined. RESULTS: Pretreatment with solCD39 significantly improved the neurological score at 72 hours compared with the vehicle group (4.4+/-0.6 versus 7.6+/-0.6, respectively; P=0.008). Cortical infarct areas were significantly reduced at multiple levels by pretreatment with solCD39. Total striatal infarct area was also significantly reduced compared with vehicle by both solCD39 pretreatment (48% mean reduction) and solCD39 treatment at 3-hour recirculation (51% mean reduction). Treatment with SolCD39 significantly reduced total infarct volume (corrected for brain swelling) by an average of 71% to 72% when administered either before ischemia or at 3 hours of recirculation compared with vehicle. Treatment with albumin significantly reduced neurological score and total, cortical, and subcortical infarction at multiple levels, as expected. CONCLUSIONS: Treatment with SolCD39, administered either before or at 3 hours after MCAO, improves neurological score and reduces infarct size compared with vehicle. A pharmacological agent of this type appears to have potential for the treatment of focal ischemic stroke.

Adenosine Triphosphatases↗
PubMed1992

[Studies on as-triazine derivatives. XVIII. Synthesis of 5,6-diaryl-1,2,4-triazine derivatives as blood platelet aggregation inhibitors].

5,6-Diphenyl-, 3,5-diphenyl-, and 3,6-diphenyl-1,2,4-triazine (as-triazine) derivatives were evaluated for inhibitory activity towards arachidonic acid-induced aggregation of rabbit blood platelet in vitro. Among the isomers, 5,6-diphenyl-as-triazine derivatives were active, therefore a phenyl substituent on the as-triazine ring at the 5- and 6-position was essential for the inhibitory activity. Thus, various 3-substituted 5,6-diaryl-as-triazines were synthesized by the nucleophilic substitution reaction of 5,6-diaryl-3-methylsulfonyl-as-triazines with O,N,C-nucleophiles. In the case of as-triazines having different aryl groups at the 5- and 6-positions, the compounds were prepared by the step-wise addition reaction of Grignard reagents with 3-methylthio-as-triazine. Among these compounds, ethyl 5-(4-methoxyphenyl)-6-phenyl-as-triazine-3-acetate (24a) and ethyl 5,6-bis(4-methoxyphenyl)-as-triazine-3-acetate (24f) showed the most potent inhibitory activity, which was almost equal to the activity of anitrazafen.

Animals↗
PubMed1993

[Studies on as-triazine derivatives. XIX. Synthesis of 2,3-diarylpyrazine 2,3-diarylpyridine derivatives as blood platelet aggregation inhibitors].

4,5-Diphenyl-2-ethoxypyrimidine (1), 3,4-diphenyl-6-ethoxypyridazine (2) and 2,3-diphenyl-5-ethoxypyrazine (3) were evaluated for inhibitory activity towards arachidonic acid-induced aggregation of rabbit blood platelet in vitro. 2,3-Diphenyl-5-ethoxypyrazine (3) exhibited significant inhibitory activity. Thus, various 5-substituted 2,3-bis(4-methoxyphenyl)pyrazines were synthesized by the nucleophilic substitution reaction of 5-chloro-2,3-bis(4-methoxyphenyl)pyrazine (9). In a similar manner, substituted 2,3-bis(4-methoxyphenyl)pyridines were prepared from 2,3-bis(4-methoxyphenyl)-6-methylsulfonylpyridine (17), which was synthesized by the cycloaddition retro Diels-Alder reaction of 5,6-bis(4-methoxyphenyl)-3-methylsulfonyl-1,2,4-triazine (16) with norbornadiene. Among the compounds prepared, 6-isopropoxy-2,3-bis(4-methoxyphenyl)-pyrazine (10f) showed the most potent inhibitory activity, which was more than the activity of anitrazafen[5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine.

Animals↗
PubMed2004

Cloning and expression of an acidic platelet aggregation inhibitor phospholipase A2 cDNA from Bothrops jararacussu venom gland.

The phospholipase A2 (PLA2, E.C. 3.1.1.4) superfamily is defined by enzymes that catalyze the hydrolysis of the sn-2 bond of phosphoglycerides. Most PLA2s from the venom of Bothrops species are basic proteins, which have been well characterized both structurally and functionally, however, little is known about acidic PLA2s from this venom. Nevertheless, it has been demonstrated that they are non-toxic, with high catalytic and hypotensive activities and show the ability to inhibit platelet aggregation. To further understand the function of these proteins, we have isolated a cDNA that encodes an acidic PLA2 from a cDNA library prepared from the poly(A)+ RNA of venom gland of Bothrops jararacussu. The full-length nucleotide sequence of 366 base pairs encodes a predicted gene product with 122 amino acid with theoretical isoelectric point and size of 5.28 and 13,685 kDa, respectively. This acidic PLA2 sequence was cloned into expression vector pET11a (+) and expressed as inclusion bodies in Escherichia coli BL21(DE3)pLysS. The N-terminal amino acid sequence of the 14 kDa recombinant protein was determined. The recombinant acidic PLA2 protein was submitted to refolding and to be purified by RP-HPLC chromatography. The structure and function of the recombinant protein was compared to that of the native protein by circular dichroism (CD), enzymatic activity, edema-inducing, and platelet aggregation inhibition activities.

Amino Acid Sequence↗
PubMed1991

Substituted pyrazolylhydrazones: a new class of platelet aggregation inhibitors.

A series of 5-pyrazolylhydrazone derivatives (I) were designed to be mixed hybrid isosteres of both BW-755C and CBS-1108 which belong to the class of dual cyclooxygenase and 5-lipoxygenase inhibitors. Pharmacological evaluation of some members of this series (Ia, 1-formyl-3,4-methylenedioxy-6-nitrobenzene-5-(1-phenyl-3-methyl-4-nit ropyrazolyl)hydrazone; Ib, 2-formylfurane-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydr azo ne;Ic, (E)-2-(formylethenylfurane)-5-(1-phenyl-3-methyl-4-nitropyrazol yl)hydrazone showed that they inhibit the in vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5 microM), collagen (5 micrograms/ml) and arachidonic acid (100 microM). Compounds Ia and Ic at 100 microM concentration showed 49% and 58% inhibition, respectively, of ADP-induced aggregation. In the arachidonic acid-induced aggregation, compounds Ia and Ib at 100 microM concentration fully inhibited platelet aggregation. All compounds significantly inhibited the collagen-induced aggregation. In contrast, indomethacin (10 microM) showed 100% and 85% aggregation inhibition against arachidonic acid and collagen, respectively, and was inactive in the ADP-induced aggregation test. These results suggest that the structure-activity relationship in this series of compounds is dependent on the hydrazone moiety at position 5 of the pyrazole ring and on the distance between the aryl ring and the pyrazole ring and that the 2-furyl ring is at the optimal distance for the maximal activity.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1999

Purification and characterization of a platelet aggregation inhibitor acidic phospholipase A2 from Indian saw-scaled viper (Echis carinatus) venom.

An acidic phospholipase A2 (EC-I-PLA2) has been purified from the Indian saw-scaled viper (Echis carinatus) venom through a combination of column chromatography and electrophoresis. EC-I-PLA2 has a molecular weight of 16000 by SDS-PAGE. It was focussed between pH 4.2 and 4.8 by isoelectro focussing. EC-I-PLA2 was non-lethal to mice and devoid of neurotoxicity, myotoxicity, anticoagulant activity and cytotoxicity. It induced mild oedema in the foot pads of mice. The purified PLA2 inhibited ADP, collagen and epinephrine induced human platelet aggregation and the inhibition was both dose and time dependent.

Adenosine Diphosphate↗