Development of prodrugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety using in vitro/in silico predictions

A nitric oxide, prodrug technology, applied in the field of predicting and developing prodrugs with a nitric oxide donor diazene-1-onium-1,2-diol moiety using in vitro/in silico

Inactive Publication Date: 2009-09-23
NOVOKIN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Esterases are traditionally known to be nonspecific

Method used

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  • Development of prodrugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety using in vitro/in silico predictions
  • Development of prodrugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety using in vitro/in silico predictions
  • Development of prodrugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety using in vitro/in silico predictions

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0179] Selection of appropriate NO-NSAID candidates

[0180] The main objectives of this example are (1) to provide in vivo data (i.e., NSAID and NO kinetic data) to train the in silico representation of the pharmacokinetic / pharmacodynamic model; (2) to validate model predictions; and (3) to select Appropriate NO-NSAID candidates for future development. NO-NSAID candidates are considered leads when they show the potential to retain their initial NSAID anti-inflammatory activity, supported by NO production and PK data, without undue gastrointestinal, cardiovascular and renal events.

[0181] The anti-inflammatory activity of non-selective and selective NSAIDs was determined indirectly using biomarkers indicative of the ability to inhibit COX-1 and COX-2 activity. Measured NO activity correlates with its potential ability to counteract NSAID side effects such as cardiovascular and renal events.

[0182] Myocardial infarction and ischemic events in high-risk patients led to the...

example 2

[0231] Physiologically based pharmacokinetic / pharmacodynamic models

[0232] The goal of this example is to demonstrate an embodiment of a physiologically based pharmacokinetic computer model in silico that incorporates all major processes and parameters and is capable of producing the output data described.

[0233] The model consists of a number of chambers, each representing a specific anatomical region. For each compound of interest in the model, each chamber has a specific volume (volume of distribution) and has a uniform internal concentration of the compound (the "well-stirred" case) ( Figure 13 ). Compounds are transported between compartments at a rate proportional to the amount of substance in the starting compartment (first order kinetics). These transports reflect diffusion and bulk flow between physiologically adjacent compartments. Many of these transports represent plasma circulation, and the sum of these flows into any compartment is equal to the sum of all...

example 3

[0238] Effects of NSAID and NO Donor on Platelet Aggregation

[0239] The objectives of this example are: (1) to study the effect of NSAID and NO donor on platelet aggregation, vasodilation and thrombosis; (2) to study the potential relationship between NSAID and NO donor in platelet aggregation, vasodilation and thrombosis. Interaction; and (3) Effect of NSAID and NO on COX function.

[0240] Methods published by Al et al. (2006), Hanson et al. (2005), Turkan et al. (2004) and Tubara et al. (2001) will be used to accomplish these goals.

[0241] The in vitro results obtained from these studies will be used to model the time course of platelet aggregation, vasodilation and thrombosis following administration of the NO-NSAID candidate.

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Abstract

The present invention provides a method of using a physiologically-based pharmacokinetic model to select a prodrug molecule (NO-X) comprising a therapeutic agent X (e.g. nonsteroidal anti- inflammatory drug, (NSAID)) and an appropriate nitric oxide donor NO. The NSAID can be a non- selective or selective cyclooxygenase inhibitor or other biocompatible compound comprising a carboxyl group. The pharmacokinetic model uses in vitro and / or in silico data to estimate an optimal set of parameters that can predict whether a particular NO-X candidate is capable of producing desirable therapeutic effects, e.g. enhanced antiif lammatory activity, reduced intestinal, cardiac and renal toxicity. Accordingly, the present invention can greatly enhance proper selection of an appropriate candidate for drug development, thereby minimizing development time and conserving costs.

Description

technical field [0001] The present invention involves the development of prodrug molecules comprising a therapeutic agent (such as a non-steroidal anti-inflammatory drug) and a nitric oxide donor. Background technique [0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat patients with various forms of arthritis since the introduction of aspirin on the market more than a century ago. The anti-inflammatory effect of NSAID is mainly mediated by inhibiting the synthesis of prostaglandin (PG) produced by cyclooxygenase (COX) (Brooks et al., 1991; Cathella-Lawson et al., 2001; Rodriguez et al. , 2001; Vane et al., 1998). PG inhibition is also a major side effect of NSAIDs, gastric ulceration (Wallace 2003). The reason is that PG is responsible for vascular homeostasis and gastrointestinal protection (Hollander, 1994; Rainsford, 1999; Schoen and Vender, 1989). [0003] In the early 1990s, COX enzymes were found to exist in two isoforms, COX-1 and COX-2. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/10
CPCG06F19/704C07D207/16G16C20/30
Inventor 谭润球克里斯托弗·马克·迪亚伯休·A·辛浦勒道格拉斯·撒切尔·瑞吉威宜展·詹姆斯·林布瑞恩·杜夫·斯洛利
Owner NOVOKIN BIOTECH
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