Anti-inflammatory compound

Because of limited space and inadequate biological data, not all the compounds or chemical series for which anti-inflammatory activity is claimed in patent specifications are discussed in this review. 

The history of the introduction of salicylates into medicine and details of the pharmacology and metabolism of these compounds have been presented in a number of reviews . The scope and nature of much recent work in this field can be assessed from papers presented at the International Symposium on Salicylates held in London in 1962 . 

The pharmacological and therapeutic relationship between acetylsalicylic acid (aspirin, /, R = COMe) and salicylic acid (/, R = H) is still not completely established. Experimentally, the anti-inflammatory activity of salicylic 

When compared directly with salicylic acid, acetylsalicylic acid has equal or slightly greater activity i3,iis,i48.i57.i75-i but there is little evidence that either compound is effective in inhibiting granuloma-type 

The therapeutic activities of acetylsalicylic acid and sodium salicylate do not appear to have been compared directly in controlled trials, although it is generally considered that the former is superiori . However, Wood , on the basis of relief of stiffness, believes that their anti-inflammatory effects are equal. Wood has also pointed out the difficulties of deter- 

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Santos FA, Rao VSN (1998) Inflammatory edema induced by 1,8-cineole in the hindpaw of rats a model for screening antiallergic and anti-inflammatory compounds. Phytomedicine 5(2) 115-119... 

CYP2C9 is the major CYP2C enzyme expressed in human liver [35] and plays a major role in the metabolism of numerous therapeutics including many weak acidic drugs such as the nonsteroidal anti-inflammatory compounds (e.g. flurbiprofen) [36] and antidiabetics (e.g. tolbutamide) [37]. In addition, CYP2C9 also metabolizes (S)-warfarin [38], lornoxicam [39] and phenytoin [37]. 

Recently, the possibility to use C60 as anti-inflammatory compound has been reported (Huang et al., 2008). Fullerene-xanthine hybrids have been studied to determine if nitric oxide (NO) and tumor necrosis factor-alpha (TNF-a) production in lipopolysaccharide (LPS)-activated macrophages can be inhibited by hybrid administration, finding positive results. The presence of xanthine moiety seems to be essential for the inhibition of LPS-induced TNF-a production, while the fullerene portion ameliorates the efficiency in LPS-induced NO production blockage, leading to a new promising class of potent anti-inflammatoiy agents. It is necessary to mention also the opposite results obtained by an amino acid fullerene derivative tested on human epidermal keratinocytes at concentration from 0.4 to 400 pg/mL. 

As examples of the range of oral bioavailability a very lipid-soluble drug such as the anticonvulsant phenytoin, or the steroidal anti-inflammatory compound prednisolone, would normally have an oral bioavailability greater than 90%, whereas a very lipid-insoluble drug such as the antibiotic, neomycin, has an oral bioavailability of less than 1%. 

Grover, P. L., and P. Sims, "Effect of Anti-inflammatory Compounds on Actomyosihadenosine Triphosphate Interaction, Biochem. Pharmacol., 19, 2251-2259(1970). 

BINAP and MeO-BIPHEP/Ru-catalyzed hydrogenation of functionalized ketones has been applied to the synthesis of more than ten important compounds, for example, antibiotics, anti-inflammatory compounds, and anticancer agents, since 1999 [59],... 

More recently, the acyl migration reaction has been studied for a range of non-steroidal anti-inflammatory compounds. For example, a detailed study has... 

As a typical example, the cHPLC-NMR separation of an extract of black beetles is shown in Figure 7.3.2.3. The methanolic extract was prepared from the vessels of one hundred black beetles (Palembus ozularis) by Marit Wahren-dorf at the Institute of Pharmaceutical Biology (Prof. Dr. Michael Wink) in Heidelberg, Germany [16]. These insects are found in South America and their vessels contain anti-inflammatory compounds which can act against asthma. As the extract was received with a non-deuterated solvent, before the injection into the chromatographic system, the solvent was evaporated and then methanol-d4 was used to dissolve the dry extract. 

Jones, R. C. and Datko, L. J. (1977) Administration of anti-inflammatory compounds in silastic capsules Inflammation Res 7, 555-562. 

Figure 2 Design and metabolism of soft corticosteroids (1) based on the inactive metabolite approach. The acid metabolites (2, 3) are inactive, but suitable substitution at the 17a-hydroxy and 17(5-carboxy functions (R h R2) can restore corticosteroid activity and also allow facile one-step deactivation. Loteprednol etabonate (4), a soft steroid, is an active anti-inflammatory compound that lacks the IOP-elevating side effect of the other steroids used ophthalmically.

As a class, PPs are considered active as antioxidant, antithrombogenic, and anti-inflammatory compounds. Many of them show an in vitro activity as scavengers of a wide range of RS, and also show inhibition of cycloxygenase and lipoxygenase (59,60), xantine oxidase (61), metalloproteases (62), and angiotensin II converting enzyme (63). All these activities are... 

Anti-inflammatory potencies were measured in mice by a 5-day modification of the Tonelli croton oil ear assay. The most potent topical anti-inflammatory compounds were 17a-heterocyclic esters in the 16a-methyl series where the 21-substit-uent was either chloro or fluoro. Thus, [21-chloro-17-(2 -furoate)] was eight-fold more potent than betamethasone valerate, while [21-fluoro-17-(2 -furoate)], [21-chloro-17-(2 -thenoate)] and 6a-fluoro-21-chloro-17-(2 -furoate)] were three-fold as potent as betamethasone valerate. 

A good correlation between gastro-intestinal side effects in man and the ulcerogenic effects in rats has been found. The anti-inflammatory compounds of the pyrazolone type, like phenylbutazone, are almost devoid of these effects, whereas non-steroidal antiinflammatory compounds of the classical phenyl acetyl type show ulcerogenic properties, which parallel their therapeutic effect. 

Anderson GD, Hauser SD, McGarity KL et al. (1996) Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J Clin Invest 97 2672-2679 Banoglu E, Okcelik Bkupeli E, Unlii S et al. (2003) Amide derivatives of [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazohnone-3-yl]acetic adds as potential analgesic and anti-inflammatory compounds. Arch Pharm Pharm Med Chem 336 251-257... 

You may have noticed that the reaction occurred only at the 2-position on pyrrole. Though all positions react with reagents like bromine, more selective reagents usually go for the 2- (or 5-) position and attack the 3- (or 4-) position only if the 2- and 5-positions are blocked. A good example is the Mannich reaction (Chapter 27). In these two examples N-methylpyrrole reacts cleanly at the 2-position while the other pyrrole with both 2- and 5-positions blocked by methyl groups reacts cleanly at the 3-position. These reactions are used in the manufacture of the nonsteroidal anti-inflammatory compounds, lolmetin and clopirac. 

A list of retention times of anti-inflammatory compounds and other acidic drugs, relative to meclofenamic acid, is given in Table 6. 

Recent studies showed that AA, EPA, and DHA could give rise to anti-inflammatory compounds such as hpoxins (LXs) and resolvins that are essential to limit and resolve inflammation (3, 4). These studies imply that a deficiency of LXs and resolvins could lead to the perpetuation of inflammation and tissue damage. In the fight of these facts, it will be interesting to study whether a subclinical deficiency of PUFAs, decreased formation of LXs and resolvins, occurs in subjects who develop the various types of infections and their complications. Because, PUFAs can inactivate enveloped viruses including influenza, it is probably worthwhile to study the effect of various fatty acids on the bird flu virus, specifically, whether increased intake of these fatty acids could reduce the risk of flu. 

AA, EPA, DHA, GLA, DGLA, LXs and resolvins suppress lL-1, lL-2, lL-6, and TNF-a prodnction by T cells (110-112, 149, 176-180). This claim suggests that EFAs/PUFAs and their metabolites function as endogenous anti-inflammatory molecules and regulate immune response and thus are likely to be of benefit in obesity, insulin resistance, atherosclerosis, metabolic syndrome X, type 2 diabetes mellitus, CHD, depression, and Alzheimer s disease that are considered as diseases of low-grade systemic inflammation (1-8, 24, 120). Some beneficial actions of PUFAs in various inflammatory conditions are because of the formation of anti-inflammatory compounds such as lipoxins, resolvins, and neuroprotectin Dl. 

Peptidomimetic modifications of the tet-rapeptide sequence have led to the conforma-tionally constrained compound (69)as a selective inhibitor of caspase-1 or interleukin-1 converting enzyme (ICE) as potential anti-inflammatory compounds (131). Recently, new non-peptide peptidomimetic diphenyl ether sulfonamides have been described as novel lead structures (70) (Fig. 15.32) (132). 

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