Pharmacological actions of ICI 180080, a novel thromboxane receptor antagonist

Jessup, C L; Jessup, R.; Wayne, Michael

doi:10.1111/j.2042-7158.1986.tb04484.x

Cited by 13 publications

(6 citation statements)

References 8 publications

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“…We have previously described the pharmacological properties of a novel series of 1,3-dioxane TXAz receptor antagonists typified by ICI 159,995 (Jessup et al 1985), ICI 180080 (Jessup et al 1986) and ICI 185,282 (Byland et al 1987;Jessup et al 1987). We now describe the activity of ICI 185,282 (5(Z)-7-([2,4,5-cis]-4-O-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl)heptenoic acid) in models of lung function in the guinea-pig.…”

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confidence: 99%

Studies In The Guinea-pig With ICI 185,282: A Thromboxane A2 Receptor Antagonist

Birch¹,

Ea²,

Calnan³

et al. 1988

Journal of Pharmacy and Pharmacology

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The effects of ICI 185,282 (5(Z)-7-([ 2,4,5-cis]-4-O-hydroxyphenyl-2-trifluoromethyl-1, 3-dioxan-5-yl)heptenoic acid) have been studied on guinea-pig platelets and pulmonary smooth muscle in-vitro and in-vivo. When tested on guinea-pig lung parenchyma in-vitro. ICI 185,282 (1 x 10(-7) M) produced a significant shift in U-46619 response curves (concentration ratio of 13:3); the antagonist (1 x 10(-5) M) did not modify histamine responses. When tested on guinea-pig trachea in-vitro ICI 185,282 (1 x 10(-7) M) caused significant inhibition of U-46619 and PGD2 responses (concentration ratios of 8.3 and 14.1, respectively); the antagonist (1 x 10(-5) M proved less effective against contractions of PGF2 alpha, LTD4 and histamine (concentration ratios of 7.0, 1.5 and 1.6). When added to guinea-pig platelet rich plasma in-vitro, ICI 185,282 (x 10(-6), 1 x 10(-5) M) caused concentration-dependent parallel shifts to the right of U-46619 aggregation curves, yielding concentration ratios of 13.6 and 141.9, respectively. In-vitro, addition of ICI 185,282 (x 10(-5) M) to indomethacin-treated pulmonary smooth muscle did not modify resting tone, neither did it induce aggregation or swelling in platelet-rich plasma preparations. When administered orally to guinea-pigs ICI 185,282 (0.1, 0.5 mg kg-1) caused a significant inhibition of U-46619-induced platelet aggregation ex-vivo which persisted greater than or equal to 8 h. In-vivo, a single oral dose of ICI 185,282 (1 mg kg-1) inhibited bronchospasm induced by U-46619, PGD2, PGF2 alpha, arachidonic acid, LTD4 and PAF; responses to histamine were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

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confidence: 99%

Studies In The Guinea-pig With ICI 185,282: A Thromboxane A2 Receptor Antagonist

Birch¹,

Ea²,

Calnan³

et al. 1988

Journal of Pharmacy and Pharmacology

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“…Results were expressed as pA2 values. Detailed pharmacological methods have been reported (Jessup et al 1986).…”

Section: Methodsmentioning

confidence: 99%

Improved synthetic routes to the novel thromboxane receptor antagonist ICI 192605: activity of synthetic 1,3-dioxane intermediates

Brown¹,

Foubister²,

Hudson³

1990

Journal of Pharmacy and Pharmacology

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A study of the synthetic routes to the thromboxane receptor antagonist ICI 192605 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid is described which led to an improvement in overall synthetic yield from 20 to 55%. Invitro thromboxane receptor antagonist data are reported for the novel 1,3-dioxane synthetic intermediates. These data indicated that shortening of the side chain in an appropriately substituted 2,2-dimethyl-1,3-dioxane (e.g. ICI 180080) from a heptenoic acid, to a hexenoic acid, had little effect on thromboxane receptor antagonist potency (pA2 = 7.5 rabbit thoracic aorta for the heptenoic acid ICI 180080 and pA2 = 6.9 for the corresponding hexenoic acid. Human platelet aggregation pA2 values were 6.7 and 7.0, respectively).

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“…1993 American Chemical Society 0 (a) K2C03, THF, A; or direct heating without solvent at 135 °C; (b) H2, Raney Ni, THF; (c) CS2, EtOH, A, 12 h; (d) K2C03, acetone, A, 5 h; (e) concentrated HC1, AcOH, H20, A, 4 h; (a') TsCl, pyridine; (b') 4 N NaOH, substituted benzyl halide, A; (cO propionic acid, H2S04, 95 °C, 1 h 30 min; (d') substituted benzyl chloride, AcONa, I2,120 °C, 12 h. derivatives 3.19 '20 An alternative preparation of compounds 3 consisted in the direct treatment of nitroanilines V with an appropriate benzyl chloride in the presence of iodine and sodium acetate without solvent at 120 °C. 21 Reduction of nitro compounds 3 was performed by catalytic hydrogenation with palladium on carbon and led to diamino compounds 4.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and structure-activity relationships of novel benzimidazole and imidazo[4,5-b]pyridine acid derivatives as thromboxane A2 receptor antagonists

Nicolaï¹,

Goyard²,

Benchetrit³

et al. 1993

J. Med. Chem.

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A series of 1-benzylbenzimidazole and 3-benzylimidazo[4,5-b]pyridine substituted in the 2-position by an alkanoic or mercaptoalkanoic acid chain was synthesized for evaluation as potential thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists. The affinity of each compound for washed human platelet TXA2/PGH2 receptors was determined by radioligand binding studies using [125I]PTA-OH. Structure-activity relationships led to the conclusions that 2-alkanoic acid derivatives were slightly more potent than 2-mercaptoalkanoic acids and that compounds possessing a 3,3-dimethylbutanoic acid in the 2-position were definitely the most potent with Ki values of 4-39 nM (11a, 11g-x, 37a, 37f-o, 23a-c). The replacement of this 3,3-dimethylbutanoic acid side chain by a shorter one led to a marked decrease of affinity (11b and 11c; Ki = 5600 and 1700 nM, respectively). Compounds of benzimidazole and imidazo[4,5-b]pyridine series displayed similar potencies (11q and 23c have Ki values of 6 and 7 nM, respectively). The interesting pharmacological profile of compound 23a (UP 116-77: 4-[3-[(4-chlorophenyl)methyl]-6-chloroimidazo[4,5-b]pyridin-2-yl]- 3,3-dimethylbutanoic acid) and its excellent tolerance led us to select this derivative for further development.

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Pharmacological actions of ICI 180080, a novel thromboxane receptor antagonist

Cited by 13 publications

References 8 publications

Studies In The Guinea-pig With ICI 185,282: A Thromboxane A2 Receptor Antagonist

Studies In The Guinea-pig With ICI 185,282: A Thromboxane A2 Receptor Antagonist

Improved synthetic routes to the novel thromboxane receptor antagonist ICI 192605: activity of synthetic 1,3-dioxane intermediates

Synthesis and structure-activity relationships of novel benzimidazole and imidazo[4,5-b]pyridine acid derivatives as thromboxane A2 receptor antagonists

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