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inhibitors. Another group of flavonoids including cirsiliol, sideritoflavone, hypolaetin glucoside, hypolaetin, oroxindin, quercetagetin glucoside, hibifolin, gossypetin
and gossypin are identified as in vitro inhibitors. It is assumed that the 5-LOX inhibition by these compounds is due to the catechol moiety present in them, which has
combined antioxidant and iron-chelating properties. Plant-derived compounds
which mimic fatty (arachidonic) acid structures also inhibit 5-LOX by binding and/
or competing at the substrate-binding site. It may also be proposed as the fatty
acid- binding cleft of 5-LOX. Thus these compounds are found to be good 5-LOX
inhibitors in vitro and in vivo.
9.2.3.2 Synthetic Inhibitors of 5-LOX
5-LOX inhibitors are grouped into three main categories: (i) Redox active compounds, (ii) Iron-ligand inhibitor with weak redox property and (iii) non-redox-type
inhibitors (Werz and Steinhilber 2005). Rational inhibitor development led to a
number of potent and orally active 5-LOX inhibitors with weak redox properties,
such as AA-861, BW755C or ICI-207968 (Werz 2004). However, these compounds
were more or less nonspecific and did not enter the market due to severe side effects.
Iron-ligand inhibitors that chelate the active site iron are potent 5-LOX inhibitors.
BW-A4C is a selective inhibitor of 5-LOX coming under the hydroxamic acid
member, with an IC 50 of 40 nM in stimulated granulocytes. However, fast inactivation and the formation of toxic nitroxide radicals make the search for alternative
ligand groups essential (Steinhilber and Hofmann 2014).
This led to the development of the hydrolytic, stable N-hydroxy urea derivative
A-64077 (zileuton), which is available in the USA for the treatment of asthma. In a
panel of cells from animals (rat, mouse, guinea pig and monkey) or humans, challenged by a variety of stimuli, zileuton gave consistently IC 50 values of 0.5–1 μM
(Rossi et al. 2010). Clinical studies reveal its potency in asthmatic conditions and
low effectiveness in other inflammatory disorders. Also attempts for increasing its
potency and oral half-life led to the development of new drug ABT-761 which
inhibits LOX with an IC 50 of 23 nM. This new drug is also found to be fivefold more
potent than zileuton in bronchospasm with an oral half-life of 16 hrs (Rossi et al.
2010).
Non-redox-type inhibitors are compound-specific and depend on the assay conditions. The efficacy of these type inhibitors (ZM 230487, L-739,010) in cells relay
on the stimuli, peroxide level and phosphorylation status of 5-LOX enzyme (Werz
2004). LOX inhibitors, linoleylhydroxamic acid (LHA) is a simple chemical derivative of the naturally occurring LA, inhibit LOXs at micromolar concentrations. A
seleno-organic compound, Ebselen, also exhibits anti-inflammatory activity.
Most of the synthetic inhibitors are designed by pharmacological companies and
are patented. The molecules include sulphonamide (a) derivatives with an IC 50 ranging from 100 to 500 nM. Diaryl-pyrimidines (b) inhibit LTB 4 production in intact rat
neutrophils with IC 50 values ranging from 0.32 to 0.97 μM. 3-O-acetyl-11-keto- -
beta-boswellic acid (AKBA) analogues (c) are also found to be good inhibitors.
Carboxyl group in 3-O-acetyl-11-keto-beta-boswellic acid was replaced by a methylcarbamoyl moiety and showed in vitro and in vivo inhibition. Another derivative
C.S. Sharanya and M. Haridas
inhibitors. Another group of flavonoids including cirsiliol, sideritoflavone, hypolaetin glucoside, hypolaetin, oroxindin, quercetagetin glucoside, hibifolin, gossypetin
and gossypin are identified as in vitro inhibitors. It is assumed that the 5-LOX inhibition by these compounds is due to the catechol moiety present in them, which has
combined antioxidant and iron-chelating properties. Plant-derived compounds
which mimic fatty (arachidonic) acid structures also inhibit 5-LOX by binding and/
or competing at the substrate-binding site. It may also be proposed as the fatty
acid- binding cleft of 5-LOX. Thus these compounds are found to be good 5-LOX
inhibitors in vitro and in vivo.
9.2.3.2 Synthetic Inhibitors of 5-LOX
5-LOX inhibitors are grouped into three main categories: (i) Redox active compounds, (ii) Iron-ligand inhibitor with weak redox property and (iii) non-redox-type
inhibitors (Werz and Steinhilber 2005). Rational inhibitor development led to a
number of potent and orally active 5-LOX inhibitors with weak redox properties,
such as AA-861, BW755C or ICI-207968 (Werz 2004). However, these compounds
were more or less nonspecific and did not enter the market due to severe side effects.
Iron-ligand inhibitors that chelate the active site iron are potent 5-LOX inhibitors.
BW-A4C is a selective inhibitor of 5-LOX coming under the hydroxamic acid
member, with an IC 50 of 40 nM in stimulated granulocytes. However, fast inactivation and the formation of toxic nitroxide radicals make the search for alternative
ligand groups essential (Steinhilber and Hofmann 2014).
This led to the development of the hydrolytic, stable N-hydroxy urea derivative
A-64077 (zileuton), which is available in the USA for the treatment of asthma. In a
panel of cells from animals (rat, mouse, guinea pig and monkey) or humans, challenged by a variety of stimuli, zileuton gave consistently IC 50 values of 0.5–1 μM
(Rossi et al. 2010). Clinical studies reveal its potency in asthmatic conditions and
low effectiveness in other inflammatory disorders. Also attempts for increasing its
potency and oral half-life led to the development of new drug ABT-761 which
inhibits LOX with an IC 50 of 23 nM. This new drug is also found to be fivefold more
potent than zileuton in bronchospasm with an oral half-life of 16 hrs (Rossi et al.
2010).
Non-redox-type inhibitors are compound-specific and depend on the assay conditions. The efficacy of these type inhibitors (ZM 230487, L-739,010) in cells relay
on the stimuli, peroxide level and phosphorylation status of 5-LOX enzyme (Werz
2004). LOX inhibitors, linoleylhydroxamic acid (LHA) is a simple chemical derivative of the naturally occurring LA, inhibit LOXs at micromolar concentrations. A
seleno-organic compound, Ebselen, also exhibits anti-inflammatory activity.
Most of the synthetic inhibitors are designed by pharmacological companies and
are patented. The molecules include sulphonamide (a) derivatives with an IC 50 ranging from 100 to 500 nM. Diaryl-pyrimidines (b) inhibit LTB 4 production in intact rat
neutrophils with IC 50 values ranging from 0.32 to 0.97 μM. 3-O-acetyl-11-keto- -
beta-boswellic acid (AKBA) analogues (c) are also found to be good inhibitors.
Carboxyl group in 3-O-acetyl-11-keto-beta-boswellic acid was replaced by a methylcarbamoyl moiety and showed in vitro and in vivo inhibition. Another derivative
C.S. Sharanya and M. Haridas