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Synthesis of novel nitric oxide (NO)-releasing esters of timolol
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Valerio Chirolia, , , Minerva R. Batugob, Stefano Biondia, Annalisa Bonfantia, Stefania Brambillaa, David C. Galeb, Lin Lib, Daniela Migliettaa, Fabio Nicolia, Ganesh A. Prassanab, Daniela Ronchettia, William F. Vernierb and Wesley K.M. Chongb
aNicOx Research Institute, Via Ariosto 21, 20091 Bresso (Milan), Italy
bPfizer Global Research and Development-La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA
Received 26 February 2009; revised 20 March 2009; accepted 23 March 2009. Available online 27 March 2009.
Abstract
A novel class of timolol derivatives with nitric oxide (NO)-donating moieties achieved chemical stability yet under physiologically relevant conditions released timolol and NO. Hindered esters A were designed and synthesized, whose ‘triggered’ release relied on enzymatic hydrolysis of the nitrate ester in A to B, that in turn cyclized to liberate timolol.
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Keywords: Beta-blocker, Vasorelaxation assay, Nitric oxide conjugate, Timolol, Trigger
Article Outline
Acknowledgements
References
Figure 1. 3-Dimensional model8 of timolol O-(2,6-dimethoxybenzoate), highlighting in the drawn oval, the carbonyl hindered to nucleophilic substitution by the flanking methoxy groups.
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Scheme 1. Hypothetical mechanism for the release of timolol: the triggering strategy undergoing through intramolecular cyclization reaction.
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Table 1.
Chemical stability in solution (buffer pH 5.7, Tween 80 0.5%, BAK 0.02%, T = room temperature) and incubation with rabbit corneal homogenate esterase liability of timolol benzoates 1–10
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a Ratio = (Area% tx/Area% t0)% by HPLC.
b Enzymatic liability was determined in presence of rabbit corneal homogenate (protein concentration was adjusted to 1 mg/mL with MCBD 153 medium obtained from Sigma–Aldrich) through the determination of timolol released into the incubating buffer at 37 °C over time. Specifically, timolol content was determined assessing the displacing activity on recombinant human β-receptors labelled with l-[4,6-propyl-3H]dihydro alprenolol16 of corneal extracts previously exposed to vehicle of test compounds.
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Table 2.
Chemical stability in solution (buffer pH 5.7, Tween 80 0.5%, BAK 0.02%, T = room temperature) and enzymatic liability of compounds 11–15
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a Ratio = (Area % tx/Area % t0) %.
b Enzymatic liability was determined as specified in Table 1.
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Table 3.
Vasodilating potency of timolol, ISMN,24 trigger compounds 11 and 12 in presence and absence of the guanylate cyclase inhibitor ODQ (10 μM)
Vasorelaxant potency was determined in rabbit aortic rings precontracted with 3 μM methoxamine. EC50 (effective concentration giving 50% of response) were estimated for each test compound from the logic curve obtained by plotting the percentage of vasorelaxant effects as a function of concentration. The EC50 could not be calculated for compounds with efficacy below 50% at the highest testable concentration of 100 μM (NC). Results are expressed as mean ± SEM of four independent experiments.
p < 0.05 versus condition in absence of ODQ.
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