Isosorbide-based aspirin prodrugs: integration of nitric oxide releasing groups.

Aspirin prodrugs and related nitric oxide releasing compounds hold significant therapeutic promise, but they are hard to design because aspirin esterification renders its acetate group very susceptible to plasma esterase mediated hydrolysis. Isosorbide-2-aspirinate-5-salicylate is a true aspirin prodrug in human blood because it can be effectively hydrolyzed to aspirin upon interaction with plasma BuChE. We show that the identity of the remote 5-ester dictates whether aspirin is among the products of plasma-mediated hydrolysis. By observing the requirements for aspirin release from an initial panel of isosorbide-based esters, we were able to introduce nitroxymethyl groups at the 5-position while maintaining ability to release aspirin. Several of these compounds are potent inhibitors of platelet aggregation. The design of these compounds will allow better exploration of cross-talk between COX inhibition and nitric oxide release and potentially lead to the development of selective COX-1 acetylating drugs without gastric toxicity.

Discovery of a "true" aspirin prodrug.

Aspirin prodrugs formed by derivatization at the benzoic acid group are very difficult to obtain because the promoiety accelerates the rate of hydrolysis by plasma esterases at the neighboring acetyl group, generating salicylic acid derivatives. By tracing the hydrolysis pattern of the aspirin prodrug isosorbide-2,5-diaspirinate (ISDA) in human plasma solution, we were able to identify a metabolite, isosorbide-2-aspirinate-5-salicylate, that undergoes almost complete conversion to aspirin by human plasma butyrylcholinesterase, making it the most successful aspirin prodrug discovered to date.

Prodrugs for amines.

The purpose of this work is to review the published strategies for the production of prodrugs of amines. The review is divided in two main groups of approaches: those that rely on enzymatic activation and those that take advantage of physiological chemical conditions for release of the drugs. A compilation of the most important approaches is presented in the form of a table, where the main advantages and disadvantages of each strategy are also referred.

Evaluation of nitrate-substituted pseudocholine esters of aspirin as potential nitro-aspirins.

Herein we explore some designs for nitro-aspirins, compounds potentially capable of releasing both aspirin and nitric oxide in vivo. A series of nitrate-bearing alkyl esters of aspirin were prepared based on the choline ester template preferred by human plasma butyrylcholinesterase. The degradation kinetics of the compounds were followed in human plasma solution. All compounds underwent hydrolysis rapidly (t(1/2) approximately 1min) but generating exclusively the corresponding nitro-salicylate. The one exception, an N-propyl, N-nitroxyethyl aminoethanol ester produced 9.2% aspirin in molar terms indicating that the nitro-aspirin objective is probably achievable if due cognisance can be paid to the demands of the activating enzyme. Even at this low level of aspirin release, this compound is the most successful nitro-aspirin reported to date in the key human plasma model.

Beta-aminoketones as prodrugs with pH-controlled activation.

N-Mannich bases have been widely applied as prodrugs of amine drugs. The analogous C-Mannich bases (beta-aminoketones) have received rather less attention probably because they are not sufficiently susceptible to elimination at pHs encountered in vivo. Compounds in which there is a thermodynamic advantage to elimination may be an exception. In this study, the physicochemical characteristics of a series of Michael amino addition adducts of chalcone and other carbonyl compounds is explored. The ketone adducts rapidly eliminate at around pH 7.4 (t(1/2) < 15 min) releasing the amine and the ketone but they are stable under acidic conditions. The Michael adducts are more lipophilic than the parent amines and have significantly suppressed ionisation characteristics at biologically relevant pH values.

Chiral separation and identification of beta-aminoketones of pharmacological interest by high performance liquid chromatography and capillary electrophoresis.

This paper describes the development and comparison of chiral methods of analysis for a series of pharmacologically active indane derivatives that have been studied in the context of the evaluation of a promising prodrug system for amines. The methods are intended for studying the differences in the pharmacokinetics of the optical isomers of these compounds. Capillary electrophoresis, using cyclodextrins as chiral selectors, and HPLC, using a Pirkle type stationary phase, were tested. Baseline separation was not achieved by HPLC, but good separations were obtained in less than 7 min, by capillary electrophoresis with phosphate buffers pH 2.5-3 using sulfated-beta-cyclodextrin or mixtures of neutral beta-cyclodextrins as chiral selectors.

A new amino-masking group capable of pH-triggered amino-drug release.

The prodrug approach is potentially useful for mitigating pharmaceutical problems--such as poor membrane permeability or stability--which commonly occur with amino drugs. On the other hand there persists a dearth of useful systems for masking amines that satisfy the prodrug requirements of good in vitro stability coupled with predictable and rapid drug release in response to a local tissue condition. This study describes an evaluation of aminoindanes as bioreversibly masked amines poised to undergo elimination to the parent amine. Several model amine and amino drug indanone derivatives were synthesised. pK(a) values were determined by capillary electrophoresis and pH rate profiles for elimination and amine liberation were measured. The aminoindanone system appears to have particular applicability to secondary amino substrates whose indanone derivatives are stable at low pH but undergo drug release at rates corresponding to first-order half-lives of <5 min at pH 7.4.

Ionisation characteristics and elimination rates of some aminoindanones determined by capillary electrophoresis.

Capillary electrophoresis (CE) has emerged as an important tool for evaluating the ionisation characteristics of compounds and their corresponding pKa values. A particular strength of CE in this context is that its relative selectivity allows one to measure the extent of ionisation of materials that are impure. In this study, using CE, we have measured the pKa values of a series of anti-inflammatory aminoindanones, which underwent degradation to indenone during the course of the determination. We subsequently monitored the elimination reactions measuring remaining indanone over the pH range 2.6-10 at constant ionic strength and temperature. The decomposition of the tertiary amino derivatives was especially fast with first-order half-lives of less than 10 min observed at pH 7.4. The resulting sigmoidal pH rate profiles can be accounted for by assuming unimolecular elimination of the protonated (slow) and neutral (fast) forms of the amines. This study provides further support for the use of CE in evaluating amino ionisation especially in cases where degradation might be expected.

Single oral dose study of two isosorbide-based aspirin prodrugs in the dog.

The objective of this study was to compare two aspirin prodrugs, isosorbide diaspirinate (ISDA) and a nitroaspirin (ISMNA), with aspirin in terms of effects on dog platelet function after administration of a single oral dose. Groups of six dogs were administered ISDA (2mg kg(-1)), ISMNA (4 mg kg(-1)) or aspirin (2mg kg(-1)). Blood was sampled at 1, 2, 4, 8, 12 and 24 h post-dosing and evaluated for capacity to generate post-clotting thromboxane (TX)B2. The aggregation response to arachidonic acid (AA) (100 microM), ADP (30 microM) or collagen (10 microg mL(-1)) was estimated at each time-point using the whole blood impedance method. Plasma ISMN following oral administration of ISMNA was also measured and compared with plasma ISMN following administration of a physical mixture of ISMN and aspirin. ISDA administration (2 mg kg(-1)) was associated with a significant reduction (P < 0.05) in serum TXB2 at 12 and 24 h (>90%) post-dosing and persistent inhibition of AA-induced platelet aggregation. ISDA administration caused a more marked depression of post-clotting TXB2 levels than aspirin in this study, although its ability to inhibit platelet aggregation was less consistent than that of aspirin. The nitroaspirin ISMNA was least effective at inhibiting platelet aggregation response or TXB2 production. The ISMN AUC(0-24 h) for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the tmax was delayed. This study indicates that the two aspirin esters cause aspirin-like effects on platelet function, probably through aspirin release, when administered orally to dogs.

Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate.

Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 degrees C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 degrees C over the pH range 1.03-9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing alpha-chymotrypsin [EC 3.1.1.1] (t(1/2)=200.9 min), carboxyl esterase [EC 3.1.1.1] (t(1/2)=31.5 min), human serum albumin (t(1/2)=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 micro g/ml; t(1/2)=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 micro g/ml; t(1/2)=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 micro M). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.