Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review
Abstract
:1. Introduction
1.1. Prodrugs
1.2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
1.3. NSAID Prodrugs
2. NO-NSAIDs
2.1. Introduction
2.2. NO-NSAIDs with Intrinsic Pharmacological Activity
- A group of glyceryl dinitrate esters (1a–c) and NONOate-containing prodrugs (2a–c) of aspirin (a = ASA), indomethacin (b = IND) and ibuprofen (c = IBU) (Figure 7) have been synthesized and evaluated in vivo and in vitro for their anti-inflammatory activity [52]. Although the ibuprofen and indomethacin esters showed in vivo activity comparable to their parent NSAIDs, the aspirin esters showed less than half the activity of aspirin. Furthermore, none of them showed in vitro inhibitory activity against COX-1; rather, they all showed inhibitory activity against COX-2 (in vitro IC50 = 0.6–9.3 μM) that was comparable to or greater than that of their parent NSAIDs. These results pose two questions: was the in vivo biological activity of these compounds due solely to the parent NSAIDs? And, second, was the GI-sparing profile only the result of NO release?
- The ethanesulfohydroxamic acid esters of indomethacin (3) and naproxen (4) were synthesized and evaluated as NO-NSAIDs [47] (Figure 8). The indomethacin ester 3 was a selective COX-2 inhibitor (IC50 = 0.42 μM) in vitro, with an in vivo ID50 of 19.1 μmol/kg compared to 11.7 μmol/kg for indomethacin. Furthermore, the non-NO-releasing hydroxamic acid ester of ibuprofen 5 showed comparable in vivo potency (78.9% inhibition of inflammation at 327 μmol/kg oral dose) to its NO-releasing hydroxamic acid (79.5% inhibition of inflammation at 327 μmol/kg oral dose). It is worth mentioning that the IC50 of 5 against COX-2 was 0.63 μM. This adds more skepticism to the accepted notion(s) that NO-releasing esters of NSAIDs are mere prodrugs and/or that NO release is essential for their GI-sparing profile. The possibility that compound 5 is a prodrug still exists, but no investigation of this possibility was performed.
- The ester of diclofenac (6) (Figure 9) contains benzofuroxan as the NO-releasing group. Ester 6 was synthesized and evaluated in vitro and in vivo for the reduction of PGE2 and TXB2 levels in plasma. This ester was found to be more effective in inhibiting PGE2 synthesis than TXB2 synthesis in vitro. This finding suggests that this NO-diclofenac ester is more selective for COX-2 [46].
- 2-Hydroxysulfamoylbenzoic acid 7 and its ethyl benzoate ester 8 (Figure 10), which are nitric oxide-releasing analogs of aspirin, were reported by Kaur et al. (2012) [53]. Although not prodrugs, these compounds show that the simple backbone of aspirin, a nonselective COX inhibitor, can be modified to become a selective COX-2 inhibitor [53]. The pharmacological evaluation of compounds 7 and 8 revealed that hydroxamic acid 8 is as a potent and a much more selective COX-2 inhibitor than celecoxib (IC50 = 0.09 μM, with more than 1000-fold selectivity). In addition, hydroxamic acid 8 was found to be a 5-lipoxygenase (5-LOX) inhibitor (IC50 = 0.4 μM). 5-LOX is an essential enzyme in the biosynthetic pathway of leukotrienes from arachidonic acid. Leukotrienes have an important role in the inflammatory process, and hence, inhibitors of 5-LOX exert an anti-inflammatory action [54]. By contrast, hydroxamic acid 7 was 10 times less potent than both celecoxib and hydroxamic acid 8, with a COX-2 selectivity comparable to that of celecoxib. Both hydroxamic acid derivatives were effective anti-inflammatory agents in vivo, with ED50 values of 23.1 μM and 24.5 μM for compounds 7 and 8, respectively, compared to 10.8 μM for celecoxib and 128 μM for aspirin. It is worth mentioning that these compounds also exhibited a time-dependent release of nitric oxide, which leads to a GIT-safe profile.
- Biava et al. (2012) reported a novel class of diarylpyrrole acetic acid derivatives, which possess the typical scaffold of classic selective COX-2 inhibitors (Figure 11). The researchers showed that 9, its hydroxyethyl and hydroxypropyl ester intermediates (10a and 10b), and their corresponding nitrate esters (11a and 11b) were all potent selective COX-2 inhibitors in vitro (IC50 = 0.019-0.083 μM) and considerably more selective than celecoxib. None of the esters (10a, 10b, 11a, and 11b) were claimed by the authors to be prodrugs of 9. Furthermore, molecular docking experiments have shown that the alcohol group in 10a and 10b and one of the oxygen atoms of the nitrates in 11a and 11b form one or more hydrogen bonds with amino acid side chains in the active site of COX-2. Furthermore, the nitrate ester 11a exhibited an in vitro vasorelaxing effect comparable to that of nitroglycerin [55]. This vasorelaxing effect can be considered the rationale behind designing NO-Coxibs.
2.3. The Role of the Linker in NO-NSAIDs
2.4. NO-NSAIDs and in Vivo Hydrolysis
3. Anticholinergic NSAIDS and AChEI-NSAIDs
3.1. Introduction
3.2. Anticholinergic NSAIDs
3.3. AChEI-NSAIDs
4. Phospho-NSAIDs
4.1. Introduction
4.2. Mechanism of Action Phospho-NSAIDs
5. Miscellaneous Agents
5.1. TEMPO-NSAIDs
5.2. HS-NSAIDs
6. Conclusions
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Name | NO donor moiety | Equivalents of NO released | Examples |
---|---|---|---|
Nitrates | –ONO2 | 1 | |
NONOate | 2 | ||
Furoxan and Benzofuroxan | 1 | ||
Sulfohydroxamic Acid | 1 | ||
Nitrosothiol Esters | 1 |
Compound | t1/2, pH 7.4 (h) | % NSAID released in plasma after 2 h | pA2** | % inhibition of Edema Volume | UI |
---|---|---|---|---|---|
Ketoprofen a | 87 | 0.882 | |||
21a–e a | 16–64 | 58.9–79.6 | 5.28–6.43 | 70–89 | 0.306–0.376 |
21f a | ND * | ND * | 7.58 | 86 | 0.299 |
Flurbiprofen b | 0 | 0.800 | |||
22a–e b | 121–505 | 17.9–51.1 | 4.73–5.79 | 79–89 | 0.130–0.230 |
22f b | ND * | ND * | 6.31 | 0 | 0.00 |
Indomethacin c | 45 | 0.55 | |||
23a–e c | 34–99 | 49.6–79.9 | 4.49–5.19 | 17–46 | 0.130–0.320 |
Atropine a,b,c | 8.02 |
Comd | % reduction in edema (Mouse ear vesicant model) [81] | Acetylcholinesterase Inhibition [72] | Plasma t1/2 (min) | Calculated LogP | |
---|---|---|---|---|---|
CEES | TPA | IC50 (μM) | |||
24a | 20 | 41 | 1.93 ± 0.64 | 204 | 7.37 |
25b | 45 | 70 | 0.83 ± 0.15 | 253 | 6.67 |
26a | 91 | 21 | 2.29 ± 0.94 | 468 | 7.87 |
27a | 90 | 24 | 0.51 ± 0.02 | 357 | 8.41 |
31a | 113 | 29 | 2.69 ± 0.15 | 111 | 7.52 |
Tacrine | - | - | 0.055 ± 0.005 | - | - |
DIC | 17 | 58 | - | - | - |
IND | 46 | 55 | - | - | - |
IBU | -15 | -33 | - | - | - |
NAP | NS | * | 104 | - | - |
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Qandil, A.M. Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review. Int. J. Mol. Sci. 2012, 13, 17244-17274. https://doi.org/10.3390/ijms131217244
Qandil AM. Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review. International Journal of Molecular Sciences. 2012; 13(12):17244-17274. https://doi.org/10.3390/ijms131217244
Chicago/Turabian StyleQandil, Amjad M. 2012. "Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review" International Journal of Molecular Sciences 13, no. 12: 17244-17274. https://doi.org/10.3390/ijms131217244