Antiplatelet Drugs in the Management of Patients with Thrombotic Disorders

Harker, Laurence A.

doi:10.1055/s-2007-1003545

Cited by 25 publications

(17 citation statements)

References 78 publications

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“…A solution of 9ab (0.70 g, 1.3 mmol) in CF3CO2H (6 mL) was stirred at room temperature for 1 h. The mixture was diluted with EtOAc and H2O, and the organic layer wa separated, washed with H20 and saturated brine, and dried over Na2S04. Evaporation of the solvent left an oil which was chromatographed on a column of silica gel using a mixture of CHC13 and MeOH (24:1) as eluent to give 10a (0.41 g, 66%) asa yellow foam: mp 54-56 °C; IR (KBr) 1725 cm"1; NMR (CDCI3) & 1.20-1.38 (6H, overlapping t, OCH2CJÍ3), 4.32 (2H, q,«7=7 Hz, OC772), 4.39 (2H, q,«Z=7 Hz, OCH2), 4.43 (2H, s, OCÜ2CO2H), 4.62 (2H, s, OCH2), 6.70-7.75 (11H, m, aromatic 77+olefinic H of (Z) isomer), 8.08 (1H, s, olefinic 77 of (E) isomer), 8.65 (1H, bs, CO2H); MS m/z 470 (M+). Anal.…”

Section: (E)-and (Z)-ethyl A-[[3-[[(ll-dimethylethoxy)carbonyl]methox...mentioning

confidence: 99%

“…The mixture was extracted with CH2CI2 to leave a solid which was dissolved in CH2CI2. The addition of hexanes gave a yellow solid which was recrystallized from a mixture of CH2CI2, hexanes, and MeOH (3:2:1) to furnish 10c (0.85 g, 39%), mp 178-182°C, as a 3:2 mixture of (E) and (Z) isomers: IR (KBr) 3060,2920,1740,1720 cm-1; NMR (DMSOde) 4.56 (2H, s, OCH2), 4.69 (2H, s, OCH2), 6.80-7.00 (2H, m, aryl H ortho to 0), 7.20-7.70 (24H, m, aryl 77 + olefinic 77), 8.08 (1H, s, olefinic H cis to acid); MS m/z 442 (M+). Anal.…”

Section: (E)-and (Z)-ethyl A-[[3-[[(ll-dimethylethoxy)carbonyl]methox...mentioning

confidence: 99%

“…The solvent was removed the residue diluted with 1 N HC1 and extracted with CH2C12 to give an oil. NMR (CDCls) & 1.23 (3H, t,J=7 Hz, OCH2Ctfa), 1.27 (3H, t,J=7 Hz, OCH2CH3), 3.30-3.60 (2H, m, CHüAr), 3.90 (1H, ddd, J -22 Hz, J' = 10 Hz, J" = 5 Hz, CflP(0)(OEt)2), 4.00-4.20 (4H, m, OCff2), 6.61 (2H, m, aromatic H ortho and para to OH), 6.83 (1H, aromatic H ortho to OH), 7.01 (1H, t, J = 8 Hz, aromatic H meta to OH), 7.28 (6H, m, aromatic H), 7.40-7.60 (4H, m, aromatic H), 7.92 (1H, s, OH); MS m/z 478 (MH+). Anal.…”

Section: Ethyla-[[3-(2-hydroxy-2-oxoethoxy)phenyl]methyl]-45diphenyl-...mentioning

confidence: 99%

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Nonprostanoid prostacyclin mimetics. 4. Derivatives of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid substituted .alpha. to the oxazole ring

Meanwell

Mj²,

Jj³

et al. 1993

J. Med. Chem.

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The 4,5-diphenyloxazole derivatives 2-4 were previously identified as nonprostanoid prostacyclin (PGI2) mimetics. A series of derivatives of 2-4 bearing substitutents at the carbon atom alpha to the oxazole ring were synthesized and evaluated as inhibitors of ADP-induced aggregation of human platelets in vitro. In the unsaturated series, the alpha-carbethoxy derivative 10a, evaluated as an equal mixture of geometrical isomers, inhibited platelet aggregation with an IC50 of 0.36 microM. Evaluation of the individual methyl ester derivatives (E)-9a and (Z)-9a revealed that (E)-9a was 10-fold more potent than (Z)-9a. In the saturated series, the alpha-carbomethoxy-substituted compound 12a inhibited platelet aggregation with an IC50 of 0.08 microM, 15-fold more potent than the unsubstituted prototype 2. The potency of 12a was found to be sensitive to variation of the methoxy moiety. The ethyl (12b) and isopropyl (12d) esters were less effective as were the acid 12e and a series of amides (12f-h). Other substituents introduced at this site of the pharmacophore included P(O)(OEt)2 (25), SCH3 (31a), S(O)CH3 (31b), SO2CH3 (31c), isopropyl (31d), phenyl (31f), and CH2OH (31i). However, none were significantly more potent inhibitors of platelet function than the parent compound 2. The results indicate the presence of a pocket in the PGI2 receptor protein that preferentially recognizes small, polar but uncharged substituents. The structure-activity correlates are suggestive of a hydrogen-bond interaction between a donor moiety on the PGI2 receptor and the methoxycarbonyl functionality of 12a that is sensitive to both the size of the substituent and its stereochemical presentation in this structural class of PGI2 mimetic. The ethyl ester 12b dose-dependently displaced [3H]iloprost from human platelet membranes and stimulated adenylate cyclase. However, the maximal stimulation was less than that recorded for iloprost, indicating that 12b functions as a partial agonist at the PGI2 receptor.

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Section: (E)-and (Z)-ethyl A-[[3-[[(ll-dimethylethoxy)carbonyl]methox...mentioning

confidence: 99%

Section: (E)-and (Z)-ethyl A-[[3-[[(ll-dimethylethoxy)carbonyl]methox...mentioning

confidence: 99%

Section: Ethyla-[[3-(2-hydroxy-2-oxoethoxy)phenyl]methyl]-45diphenyl-...mentioning

confidence: 99%

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Nonprostanoid prostacyclin mimetics. 4. Derivatives of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid substituted .alpha. to the oxazole ring

Meanwell

Mj²,

Jj³

et al. 1993

J. Med. Chem.

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“…The therapeutic benefit of inhibitors of blood platelet aggregation in a number of pathological conditions that involve thrombotic or thromboembolic components has been established in clinical studies using primarily aspirin but also dipyridamole and, more recently, ticlopidine. [2][3][4][5][6][7][8][9][10][11][12][13] However, these studies have also demonstrated the inadequacies of the drugs currently available for clinical use and provide an impetus to discover and develop more efficacious agents with a reduced incidence of side effects. [13][14][15] For some time, we have been exploring the potential of a series of imidazo [4,[5][6] quinolin-2-one derivatives as antithrombotic agents.1•16-21 The prototype of this structural class, 1, possesses potent intrinsic blood platelet aggregation inhibitory activity that is readily enhanced by introduction of substituents at the 6, 7, 8 and 9 positions.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5][6][7][8][9][10][11][12][13] However, these studies have also demonstrated the inadequacies of the drugs currently available for clinical use and provide an impetus to discover and develop more efficacious agents with a reduced incidence of side effects. [13][14][15] For some time, we have been exploring the potential of a series of imidazo [4,[5][6] quinolin-2-one derivatives as antithrombotic agents.1•16-21 The prototype of this structural class, 1, possesses potent intrinsic blood platelet aggregation inhibitory activity that is readily enhanced by introduction of substituents at the 6, 7, 8 and 9 positions. 16 The most potent, broad-spectrum inhibitors of blood platelet function to emerge from this study are compounds appended with functionalized side chains linked to the heterocycle through an oxygen atom at the 7 position of the nucleus.1 •17 The side-chain terminus of this structural type is thought to interact with a secondary binding site in the platelet low Km, cGMP-inhibited cAMP phosphodiesterase enzyme that appears to be the site of action of these agents.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of blood platelet cAMP phosphodiesterase. 4. Structural variation of the side-chain terminus of water-soluble 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives

Meanwell

Hewawasam²,

Thomas³

et al. 1993

J. Med. Chem.

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1-(Cyclohexylmethyl)-4-[4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b] quinolin-7-yl)oxy]-1-oxobutyl]piperazine (2) was previously identified as a potent, water-soluble inhibitor of human blood platelet cAMP phosphodiesterase and of induced aggregation in vitro that demonstrated effective antithrombotic activity in animal models of thrombosis. Although 2 exhibited 25% oral bioavailability in rats, pharmacokinetic studies conducted in monkeys revealed that the parent compound was less than 5% bioavailable, the result of extensive first-pass biotransformation in the liver. In an effort to identify potent platelet aggregation inhibitors with enhanced metabolic stability, the side-chain amide moiety of 2 was replaced with chemically more stable urea (6a-s), sulfonamide (13a-m), sulfone (19a-r), and tetrazole (23a-s) moieties. Many representatives from each of these structural types effectively combined potent inhibition of ADP-induced human platelet aggregation in vitro with excellent aqueous solubility, and several are superior to 2. Within each series, the N-(cyclohexylmethyl)-, N-(2-ethylbutyl)-, N-benzyl-, and N-(4-fluorobenzyl)-substituted derivatives were evaluated for in vitro metabolic stability by incubating with the S-9 fraction of monkey liver for 2 h, and the extent of biotransformation was compared with that of the prototype 2. The sulfone 19e and the tetrazoles 23e, 23g, 23j, and 23q were significantly more stable than 2 under these conditions, and 19e and 23e were selected for evaluation in vivo. Tetrazole 23e exhibited 72% bioavailability following ip administration to rats compared with 35% bioavailability for 2 and 19e under the same conditions. However, the oral bioavailability of 19e and 23e in the rat was estimated to be only 3%, suggesting that 19e and 23e are less readily absorbed from the gastrointestinal tract than 2.

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Prevention of thrombus formation on biomaterials exposed to blood using different antiplatelet drugs: Experimental study in dogs

Escudero

Álvarez

Haro

et al. 1994

J. Biomed. Mater. Res.

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An ex vivo shunt, established in dogs between both femoral arteries and right atrium, has been used to quantify the platelet deposition on six prosthetic materials used in the construction of cardiovascular prostheses: highly porous knitted Dacron (intervascular HP 800, 1400 mL/cm2/min/120 mm Hg), low-porosity woven Dacron (intervascular LP 200, 200 mL/cm2/min/120 mm Hg), double velour knitted Dacron, Avcothane 51 elastomere, and the mesothelial and epipericardial surfaces of bovine pericardium. In the search for a method to prevent platelet thrombi formation on these materials, we studied four groups of dogs: group 1 (control), group 2 (5 mg/kg body weight (BW)/day acetylsalicylic acid), group 3 (20 mg/kg BW/day acetylsalicylic acid), and group 4 (5 mg/kg BW/day acetylsalicylic acid plus 5 mg/kg BW/day dipyridamole). Platelets were labeled with 111In-oxine. The least thrombogenic material was Avcothane 51 elastomere. The only effective treatment for reduction of platelet deposition on the six materials was 5 mg/kg BW/day of acetylsalicylic acid. The dose used in group 3 only decreased the deposition of platelets on three of the six materials studied. The treatment employed in group 4 did not significantly reduce the deposition of platelets on any of the materials when compared with the control group.

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Antiplatelet Drugs in the Management of Patients with Thrombotic Disorders

Cited by 25 publications

References 78 publications

Nonprostanoid prostacyclin mimetics. 4. Derivatives of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid substituted .alpha. to the oxazole ring

Nonprostanoid prostacyclin mimetics. 4. Derivatives of 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid substituted .alpha. to the oxazole ring

Inhibitors of blood platelet cAMP phosphodiesterase. 4. Structural variation of the side-chain terminus of water-soluble 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one derivatives

Prevention of thrombus formation on biomaterials exposed to blood using different antiplatelet drugs: Experimental study in dogs

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