455. The strength of heterocyclic bases

Albert, Adrien; Goldacre, R. J.; Phillips, John William Cole

doi:10.1039/jr9480002240

Cited by 418 publications

(226 citation statements)

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“…3,5-,8-Pyrazolethylamine, which stimulates secretion in the dog stomach (Grossman et al, 1952), was active in the rat but much less so than histamine. The lower basicity or reactivity of the pyrazole ring compared with imidazole (Albert, Goldacre & Phillips, 1948) may account for the quantitative difference. Although modification of the imidazole ring results in a marked fall in activity, the spatial relationship of the basic groups in the ring and side chain do not appear to be critical for the gastric receptor.…”

Section: Discussionmentioning

confidence: 99%

Receptors Mediating Some Actions of Histamine

Ash

Schild

1966

British Journal of Pharmacology and Chemotherapy

621

203

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Section: Discussionmentioning

confidence: 99%

Receptors Mediating Some Actions of Histamine

Ash

Schild

1966

British Journal of Pharmacology and Chemotherapy

621

203

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“…The longer than expected N...I distances [2.982 (1) and 3.098 (1)A] observed for a similar complex of phenazine [pKa = 1.2 (Albert, Goldacre & Phillips, 1948)] with iodine (Uchida, 1967;Uchida & Kimura, 1984) are probably also the result of steric shielding, in this case involving the H atoms at the l, 4, 5 and 8 positions of the fused ring system.…”

Section: Commentmentioning

confidence: 99%

Molecular complexes of 1,4-diazines with iodine

Bailey¹,

Buchanan²,

Pennington³

1992

Acta Crystallogr C

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“…After protonation of amidines at the double-bonded nitrogen, cations are formed that are highly stabilized by mesomerism. Amidines are very strong bases (Albert et al, 1948) and protonated under physiological conditions. By introduction of an oxygen atom in the amidine functional group, the basicity is lowered by 5 pK a value.…”

mentioning

confidence: 99%

Characterization of in Vitro Biotransformation of New, Orally Active, Direct Thrombin Inhibitor Ximelagatran, an Amidoxime and Ester Prodrug

Clement¹,

Lopian²

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:N-Hydroxylated amidines (amidoximes) can be used as prodrugs of amidines. The prodrug principle was developed in our laboratory for pentamidine and had been applied to several other drug candidates. One of these compounds is melagatran, a novel, synthetic, low molecular weight, direct thrombin inhibitor. To increase the poor oral bioavailability due to its strong basic amidine functionality selected to fit the arginine side pocket of thrombin, the less basic N-hydroxylated amidine was used in addition to an ethyl ester-protecting residue. The objective of this investigation was to study the reduction and the hydrolytic metabolism of ximelagatran via two mono-prodrugs (N-hydroxy-melagatran and ethyl-melagatran) to melagatran by in vitro experiments. New high-performance liquid chromatography methods were developed to analyze all four compounds. The biotransformation of ximelagatran to melagatran involving the reduction of the amidoxime function and the ester cleavage could be demonstrated in vitro by microsomes and mitochondria from liver and kidney of pig and human, and the kinetic parameters were determined. So far, one enzyme system capable of reducing N-hydroxylated structures has been identified in pig liver microsomes, consisting of cytochrome b 5 , NADH-cytochrome b 5 reductase, and a P450 isoenzyme of the subfamily 2D. This enzyme system also reduces ximelagatran and N-hydroxy-melagatran. The participation of recombinant human CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4 with cytochrome b 5 and b 5 reductase in the reduction can be excluded. In summary, ximelagatran and N-hydroxy-melagatran are easily reduced by several enzyme systems located in microsomes and mitochondria of different organs.Melagatran is the active form of the novel, oral thrombin inhibitor ximelagatran (Gustafsson et al., 2001). Melagatran has suboptimal bioavailability because of the presence of a carboxylic acid, a secondary amine, and an amidine residue resulting in a charged molecule at physiological pH values. The prodrug ximelagatran was developed with a view to improving absorption. Ximelagatran comprises an ethyl ester group in place of the carboxylic acid and an N-hydroxyamidine group in place of the amidine. After protonation of amidines at the double-bonded nitrogen, cations are formed that are highly stabilized by mesomerism. Amidines are very strong bases (Albert et al., 1948) and protonated under physiological conditions. By introduction of an oxygen atom in the amidine functional group, the basicity is lowered by 5 pK a value. Amidoximes have been used as prodrugs for certain amidine-containing drugs, including pentamidine derivatives (Clement, 1993) and sibrafiban (Weller et al., 1996). It has been shown that certain amidoximes are rapidly reduced in vitro and in vivo to the amidines (Clement et al., 1988(Clement et al., , 1992Hauptmann et al., 1988). More recently, it has been demonstrated that the model compound benzamidoxime is reduced by microsom...

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455. The strength of heterocyclic bases

Cited by 418 publications

References 0 publications

Receptors Mediating Some Actions of Histamine

Receptors Mediating Some Actions of Histamine

Molecular complexes of 1,4-diazines with iodine

Characterization of in Vitro Biotransformation of New, Orally Active, Direct Thrombin Inhibitor Ximelagatran, an Amidoxime and Ester Prodrug

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