Aldose Reductase: A Multi-disease Target

Jaiprakash N Sangshetti*1, Rashmi S. Chouthe1, Nikhil S. Sakle1,Indrajeet Gonjari2, Devanand B Shinde3

1 Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh,Aurangabad-431001

2 Government College of Pharmacy Karad (MS)

3 Department of Chemical Technology, Dr. B. A. M. University, Aurangabad-431004

* Correponding Author email: jnsangshetti@rediffmail.com

Abstract:

Aldose reductase (AR) is an enzyme that catalyzes the rate

limiting step of the polyol pathway of glucose metabolism,

besides reducing glucose to sorbitol, reduces a number of lipid

peroxidation derived aldehydes and their glutathione conjugates.

Recent studies suggest that apart from its involvement in

diabetic complications, AR's catalytic activity plays a key role

in a number of inflammatory diseases such as atherosclerosis,

sepsis, asthma, uveitis, and ovarian cancer. Furthermore, AR is

over expressed in human cancers such as liver, colon, breast, and

cervical. AR inhibitors have undergone up to phase-III clinical

trials for diabetic complications, they are also reported as safe

anti-inflammatory drugs. Therefore the future use of AR

1

inhibitors in down-regulating major multidiseases and

inflammatory pathologies such as cancer and cardiovascular

diseases could relieve some of the major health concerns of

worldwide.

Key words: Aldose reductase inhibitors, Diabetic neuropathy,

inflammatory pathologies, Polyol pathway.

Introduction-

Glucose is metabolized mostly in vivo by the glycolytic system, but

an extremely small part is metabolized through the polyol pathway

(Fig 1). In polyol metabolic pathway Aldose reductase (AR)

catalyzes the reduction of glucose to sorbitol with NADPH as a

cofactor. The metabolism of glucose consists of two steps, in

which glucose is converted into sorbitol and further into

fructose. The rate-limiting enzyme of this pathway is AR, which

belongs to the aldo-keto reductase family [1,2], AR is

distributed widely throughout the body, including areas such as

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the adrenal gland [3], arterial smooth muscle[4], ovary[5] ,

testis[6] and target organs of diabetic complications such as

the lens, retina, kidney [3,5] and peripheral nerves [5,6]. A

physiological roles, AR regulates osmotic pressure in the kidney

medulla [7], steroid metabolism in the adrenal gland and

reproductive organs [4,8] detoxication of aldehyde compounds such

as 4-hydroxynonenal (HNE) in the vascular wall in case of giant

cell arteritis [9], and regulation of harmone in the ovary [8].

In a hyperglycemic state, the glucose metabolism through the

polyol pathway is accelerated [2]. Activation of AR enzymes

causes accumulation of sorbitol in tissues which does not

diffuses through cell, leads to various diabetic complications

and also involved in the pathogenesis of CVS, CNS, cancer and in

some of the inflammatory conditions.

In addition, the excessive consumption of NADPH associated with

the enhanced enzymatic reaction of AR results in suppression of

NO synthesis [13] and reduced glutathione (GSH) production [14].

The decrease in the amount of NO, which acts as a vasodilating

mediator, causes circulatory disorders. The decrease in the

amount of GSH leads to an increase in reactive oxygen species3

(ROS), resulting in impairment of endothelial function. Hence,

acceleration of the polyol pathway metabolism of glucose is an

important factor in the onset and progression of diabetic

complications such as neuropathy, vascular disorders and other.

Thus, various AR inhibitors have been developed to correct this

metabolic abnormality.

A number of cardiac disorders, including myocardial ischemia,

ischemia–reperfusion injury, congestive heart failure, cardiac

hypertrophy and cardiomyopathy have been linked to increased ROS

generation and lipid peroxidation within myocardium and studies

have been conducted in order to determine the role of aldose

reductase (ALR2) in myocardial metabolism during ischemia [15].

Furthermore, ALR2 has been reported to be implicated with

inflammation [16, 17], mood disorders [18], renal insufficiency

[19], ovarian abnormalities [20] and human cancers such as liver,

breast, ovarian, cervical and rectal cancers [21, 22].

Considering the involvement of AR in etiology of various diseased

conditions of 21st century, intense efforts have been taken to

discover ARI of distinct chemical structures.

Aldose reductase structure-4

ALR2 is a 316 amino acid enzyme and its molecular weight is found

to be 36 kDa. The primary structure of ALR-2 was first determined

in rat lenses [23]. In 1992, the first two ALR2 structures were

published; the human placenta ALR2 [24] and that of porcine ALR2

[25]. These structures were composed of a similar α/β-barrel with

a core of eight parallel β-strands connected by peripheral α-

helices. The active site of AR is located at the C-terminal face

of the barrel which is apt for efficient interaction with NADPH,

a cofactor required for AR’s reduction reactions. The

nicotinamide ring was centered in the active site cavity. This

highly hydrophobic active site pocket is formed by aromatic

residues (Trp20, Tyr48, Trp79, Trp111, Phe121, Phe122 and

Trp219); apolar residues (Val47, Pro218, Leu300 and Leu301);

polar residues (Gln49, Cys298and His110); and three possible

proton donors, which were Tyr48, His110 and Cys298, were also

identified. This protein, which is called aldose reductase-like-1

protein, AKR1B10 or ARL-1 having same size as ALR2, and its amino

acid sequence is 70% identical to that of ALR2. Apart from the

amino acid sequence similarity, all of the key amino acids

proposed to be responsible for ALR2 enzymatic activities are

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conserved in this protein. They include Ser159, Asn160, Gln183,

and Lys262 for cofactor NADPH binding, Tyr48 and His110 as

potential hydrogen donors, and active site residues Lys77,

Tyr209, and Cys298. Therefore, similar to ALR2, ARL-1 can

efficiently reduce aliphatic and aromatic aldehydes, and it is

less active on hexoses. While ALR2 mRNA is found in most tissues

studied, ARL-1 is primarily expressed in the small intestines and

in the colon, with a low level of its mRNA in the liver, thymus,

prostate and testis. Since ARL-1 is predominantly found in the

small intestines and in the colon, it is likely to be responsible

for inactivating toxic aldehydes in digested food before the

nutrients are transported to other organs [26,91,96].

Role of ARIs in diabetic complications-

ARIs in diabetic neuropathy-

Neuropathic pain can be described as a sensation of paresthesia

and burning that is caused by the sustained, abnormal processing

of CNS neuronal input [27]. The constant pain can lead to other

health issues, such as constant fatigue, depression and anxiety

which decrease the quality of life in these patients. Neuropathy

can occur both from damage to the nerve parenchyma and from

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neuronal ischemia leading to abnormalities of microvessels [28].

In the peripheral nerves, the decrease of myo-inositol content

is concerned with the excessive accumulation of sorbitol [10],

which leads to changes in Na+, K+, ATPase pump activity present

on the axonal membrane [11,12]. These changes result in the

intra-axonal Na+ accumulation and reduction in trans-membrane Na+

conduction. Impairment in the function alters the membrane

potential that ultimately result in the axonal death [92].

Vincent et al. [29] pointed the major role of oxidative stress in

the pathogenesis of diabetic neuropathy. Oxidative stress may be

derived from excessive flow through the polyol pathway or advance

glycation end products (AGE), mediated protein kinase C (PKC)

activation and uncoupling of the respiratory chain in the

mitochondria. The polyol pathway plays an important role in the

development and progression of diabetic neuropathy.

ARI in diabetic retinopathy-

Diabetic retinopathy is a common cause of vision loss which is

characterized by retinal capillary cell loss and formation of

acellular capillaries, capillary basement membrane thickening,

increased vascular permeability and disruption of blood-retinal

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barrier, and increased leukocyte adhesion to endothelial cells

[95]. The selective destruction of retinal pericytes has been

linked to the production of sorbitol and galacticol [30].

Accumulated sorbitol within retina may cause osmotic stress,

resulting in excessive hydration, gain of Na+ and loss of K+ ions

and also the byproducts of polyol pathway, fructose-3-phosphtae

and 3-deoxyglucosone are powerful glycosylating agents that enter

in the formation of AGEs, which are an important factor for the

pathogenecity of diabetic retinopathy [93]. The use of ARIs in

many animal models has prevented the early activation of

complement in the wall of retinal vessels, apoptosis of vascular

pericytes and endothelial cells and the development of acellular

capillaries [31]. Osmotic stress in the ocular lens deranges the

cell membrane, resulting in the leakage of amino acids, GSH and

myo-inositol to induce cataract formation [32]. Additionally,

ALR2 is implicated with diabetic retinopathy via a plethora of

signaling pathways such as the activation of nuclear factor kappa

B (NF-kβ) and further regulating the monocyte chemotactic

protein-1 (MCP-1) which contributes to the formation of diabetic

epiretinal membranes [33]. Also in the retina, increased ALR2

8

activity enhances oxidative stress and upregulates retinal

vascular endothelial growth factor (VEGF). Another implication of

ALR2 in diabetic retina is considered to be through the

activation of poly (ADP-ribose) polymerase (PARP). Activation of

PARP tends to be a mechanism in the pathogenesis of diabetic

retinopathy, endothelial and myocardial dysfunction and

peripheral neuropathy [34, 35]. The use of fidarestat, an ARI

counteracts diabetes-associated retinal oxidative-nitrosative

stress and PARP formation supporting an important role for AR in

diabetes and rationale for the development of ARIs for

counteraction of polyol pathway [94].

ARI in diabetic nephropathy-

Renal polyol accumulation has also been suggested to be involved

in diabetic nephropathy [36]. Interaction between hyper-glycemia-

induced oxidative stress from AR activation, increases the

formation of AGEs and activation of vascular PKC iso-forms

ultimately result in microvascular diabetic complications. PKC

activation may induce an increase in glomerular prostaglandin E

production and loss of mesangial cell contractility leading to

hyperfiltration and glomerular dysfunction [37]. Furthermore, the

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decrease in glomerular filtration rate may implicate the renal

VEGF, since its levels increase in preclinical models of diabetes

[28]. A number of ARIs like tolrestat, sorbinil and ponalrestat

have been studied in diabetic animals. Oral administration of

tolrestat in galactosemic animals revert capillary lesions,

pericyte degeneration, endothelial cell proliferation,

accellularity, capillary dilation, and microaneurysm formation.

Sorbinil and ponalrestat, were reported to prevent glomerular

basement membrane thickening (GBMT) and albuminuria development

in diabetic rats [96-98]. Clinical studies of ARIs in the

diabetic complications delayed the progression of symptoms of the

disease also showed reduced urinary albumin excretion rate after

treatment for 6 months or 5 years [99-100].

Role of ARI in non-diabetic diseases-

ARI in inflammatory pathogenesis-

AR is mainly involved in the metabolizing glucose, but it also

shows its involvement in catalyzing the reduction of a wide range

of substances such as lipid aldehydes generated during lipid

peroxidation and their glutathione (GSH)-conjugates,

phospholipids, atherogenic aldehydes, and steroids [101]. During

10

the inflammation a pro-inflammatory endotoxin lipopolysacharides

(LPS) and component of gram negative bacterial cell wall is

released in the circulation and stimulates toll like receptor-4

(TLR-4) [38]. LPS is interact with cluster of differentiation 14

(CD 14) and it leads to increase transcription of inflammatory

and immune response genes, activation of NK-kB and further

stimulate IL-1, TNK-α, PG and NO [39]. ALR2 inhibition suppressed

NF-kB mediated transcription in LPS treated cells of macrophage,

and further reduced the production of IL-1 and TNK-α. There are

reports that, apart from the down regulation of NF-kB also

indicate as possible mechanisms the modulatory effect on

prostaglandin E2 production, cycloxyganase-2 (COX-2) activity and

PKC pathways [40], reduced production of NO and suppression of

the LPS-induced over expression of inducible NO synthetase mRNA

[41]. Inhibition of ALR2 represents a useful approach for

prevention and treatment of ocular inflammatory response such as

uveitis [42] and endotoxin-related inflammatory diseases [43].

Aldose reductase inhibitors (AKR1B1) give a novel therapeutic

approach to treat inflammatory airways diseases [89].

ARIs in ischemic conditions-

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Earlier studies have demonstrated that AR plays a key role in

mediating ischemia-reperfusion (I/R) injury [104]. During low-

flow ischemia there is increase in the NO level. Some of the

studies have shown that NO donors increase AR activity in

cultured cells. The cascades of events like increase in cytosolic

NADH/NAD+ ratio and decrease in glycolysis and ATP level leads to

ischemic injury [101]. Also ischemia injury causes accumulation

of sorbital intermediates causes cell death [102]. Hwang et al.

studied the central role of AR in transgenic mice expressing

human AR (ARTg) during ischemia reperfusion injury. The data

strongly support the pharmacological inhibition of AR in ARTg

mice. It reduced cytosolic NADH/NAD+ ratio and further

consequence, also reduced ischemic injury and improved functional

recovery [103]. The expression of AR is regulated by a number of

transcription factors, such as osmotic response element binding

protein (OREBP) and NF-kB, by binding to the AR promoter possibly

under osmotic or oxidative stress conditions associated with

ischemia [44,45,46].

Some of the studies have shown the influence of ischemia on

cardiac ALR2 activity, also the effect of flux via the polyol

12

pathway on myocardial glucose metabolism [47,48]. Pharmacological

inhibition of ALR2 could be cardio-protective, as it seems to be

a key component of myocardial ischemic injury, and could reverse

the increased NADH/NAD+ ratio (as a result of reduced NAD+ use by

sorbitol dehydrogenase SDH) and therefore improving myocardial

glucose metabolism by increasing glycolysis and ATP production.

Additionally, ARIs partially augment intracellular sodium and

calcium during ischemia, secondary to increased glucolytic

metabolism and the observed changes in intracellular sodium were

partly attributable to increases in Na+, K+-ATPase activity.

Therefore, it was suggested that ARIs could be used

therapeutically in treating patients with myocardial infarction.

ARIs applied during the pre-ischemic phase improved cardiac

performance and attenuated myocyte damage, while inhibitors

applied during the reperfusion phase had limited effect on

cardiac performance but significantly attenuated myocyte damage

by reducing oxidative stress elicited by ischemic insult and

reoxyganation. Therefore, the use of ARIs in the post ischemic

reperfusion phases protecting ischemic heart from ischemic

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reperfusion injury. ALR2 in the ischemic heart may play a role in

the protection against ROS produced during ischemia reperfusion.

Proliferation of vascular smooth muscle cells (VSMCs) is one of

the key features of atherogenesis, restenosis, and hypertension.

It is characterized by endothelial dysfunction due to

cardiovascular risk factors or mechanical injury, resulting in

the expression of several growth factors and cytokines that exert

mitogenic effects on VSMCs [49]. Inhibition of the enzyme

prevented DNA synthesis and cell growth in culture and intimal

hyperplasia in vivo. The absence of ALR2 in inactive VSMCs and its

high expression in VSMCs proliferating in culture suggested that

the enzyme is specifically up regulated during growth. The

association of ALR2 with cell growth was further supported by the

observation that after balloon injury, the proliferating cells of

the neointima showed high levels of expression of this enzyme.

The mechanism of the regulatory effect of ALR2 on cell growth was

further studied and it was found that ARIs prevented the tumor

necrosis factor-α (TNF-α) induced activation of NF-kB, with final

result the attenuation of VSMCs proliferation not by increasing

cell death but by inhibiting their growth [50].

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ARI in Renal insufficiency-

ALR2 had an effect on transforming growth factor (TGF) β1-induced

synthesis of fibronectin and type IV collagen in the mesangial

cells under normoglycemia [51]. This could be due to the

modulation of activation of c-Jun N-terminal kinase (JNK) and p38

signal transduction pathways and transcription factor AP-1. ARIs

such as sorbinil or zopolrestat reduced the activation of JNK, p-

38 MAPK and AP-1 induced by TGF-β1. The production of

extracellular matrix (ECM) components in the mesangial cells

under normal glucose concentration by ALR2, suggested that it

might play a role in pathogenesis of nondiabetic

glomerulosclerosis. ECM proteins deposition and obliteration of

glomerular capillaries, is considered to be the final pathway

leading to the progressive loss of renal function in several

kidney diseases. The increased ALR2 activity in such cases may

affect the peritoneal membrane from the vascular side in patients

undergoing peritoneal dialysis. In these cases injury of the

peritoneal membrane with structural changes and functional

decline, such as ultra filtration occur. Further studies are

needed to clarify the role of ALR2 and the potential protective

15

role of its inhibition in patients with chronic kidney diseases

treated with peritoneal dialysis [52]. Increases in the AGE–RAGE

axis have been demonstrated in renal failure both in animal

models and in human subjects. Large AGE proteins unable to enter

the Bowman’s capsule are capable of binding to receptors on

endothelial and mesangial cells and to the mesangial matrix.

Activation of RAGE induces production of a variety of cytokines,

including TNFβ, which mediates an inhibition of metalloproteinase

and increases production of mesangial matrix, leading to renal

failure [105].

ARI in ovarian diseases-

The mammalian ovary is susceptible to damage from the

accumulation of galactose and galactose metabolites like Gal-1-P,

galactitol, and UDPgal, due to unusually high local

concentrations of enzymes responsible for its metabolism [53].

Apart from its major metabolic pathways that include the enzymes

galactokinase, galactose-1-phosphate uridyltransferase (GALT),

and UDP-galactose-4-epimerase, the polyol pathway is also

involved and therefore galacticol is produced. Galacticol is

poorly metabolized and its accumulation leads to ovarian toxicity

16

due to osmotic imbalance and GSH depletion. At this point it must

be noted that the affinity of ALR2 for galactose is relatively

low, and high intracellular concentrations of galactose are

required as in galactosemia, an inherited disorder due to GALT

deficiency [54]. ARIs have been observed to cause a reversal of

galactose-induced toxicity in animals via the reduction in

galactitol levels. They have been found to prevent ovarian

dysfunction in rats fed with high galactose diet [55].

ARI in cancer-

It was found that about 29% of the liver cancers over expressed

ALR2, and about 54% of them over expressed a novel ALR-1 [55].

The incidence of the ALR2 over expression and activation in these

cases was suggested to render cancer cells resistant to

anticancer drugs and that ARIs could reserve this resistance.

Resistance towards anticancer drugs, such as the anthracycline,

daunorubicin and doxorubicin, is a major problem in the

chemotherapy of cancer and it may be due to biotransformation

enzymes, such as ALR2, that catalyze carbonyl reduction of

anthracyclines into their inactive alcohol metabolites [56]. ALR2

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up regulation can be considered as one non classical mechanism of

resistance to chemotherapy.

Colon cancer is a complex multi step process involving

progressive disruption of homeostatic mechanisms controlling

intestinal epithelial proliferation, differentiation, and

programmed cell death. One of the main features of colon cancer

is the over expression of the inducible COX-2 [57] that catalyzes

the first two steps in the biosynthesis of prostaglandins from

arachidonic acid. The de novo synthesis of COX-2 is triggered by

the exposure of cells to certain stimuli, such as cytokines and

growth factors, which lead to induction of altered synthesis of

prostaglandins followed by uncontrolled colon epithelial cell

proliferation. A major signaling pathway associated with the

oxidative stress and inflammation is the activation of NF-kβ by

growth factors (such as fibroblast derived growth factor bFGF and

platelet-derived growth factor PDGF) or inflammatory cytokines

(such as TNF-β). Modulation of NF-kβ may play a central PDGF role

in the mitogenic process initiated by ROS and related oxidants in

colon cancer. Additionally, the expression of ALR2 is enhanced in

various types of cancer as previously mentioned. Therefore, the

18

role of ALR2 in mediating the growth factor induced expression of

COX-2 and production of prostaglandin E2 was investigated

[58,59]. Inhibition of ALR2 significantly (>90%) prevented the

production of prostaglandin E2 by induced by PDGF. Finally, it

was demonstrated that ALR2 is an obligatory mediator of growth

factor induced colon cancer cell proliferation and its inhibition

prevents the S phase of cell cycle, which is an important stage

required for cell growth. In addition another study was conducted

[60] in order to clarify the role of ALR2 in mediating the TNF-a-

induced production of prostaglandin E2 in colon cancer Caco-2

cells. In conclusion, ALR2 was found to be an obligatory mediator

of the inflammatory changes caused by growth factors- and

inflammatory cytokines- induced cytotoxicity in colon cancer and

therefore ALR2 inhibition may represent a novel therapy for colon

cancer. Adrenal tumors are divided into benign adenomas, which

are extremely frequent, and rare malignant carcinomas, accounting

for 0.05–0.2% of all cancers and with an extremely poor

prognosis, the survival rate being 20% at 5 years [61]. As the

adrenal gland is a major site of expression of ALR2, a study was

contacted in order to show whether changes in its expression

19

could be associated with adrenal disorders [62]. It was found

that ALR2 gene is differentially expressed in benign vs.

malignant tumors in adrenal cortex and that ALR2 gene expression,

measured at mRNA and protein levels, is strongly decreased in

adrenal cortex carcinomas, compared with that in adenomas. The

low expression of ALR2 in carcinomas may be due to chr omosome

alterations, including mutations or rearrangements that could

reduce expression of the gene or due to deregulation of the

mechanisms underlying the control of the gene expression and it

was the first time that it is suggested that cAMP is a regulator

of ALR2 expression in human adrenocortical cells. Additionally,

it was reported that the transcription factor cAMP-responsive

element-binding protein (CREB) was decreased at the protein level

in adrenal cortex carcinomas [63], and cAMP- stimulated PKC

activity is lower in adrenal cancers than adenomas [64]. It must

be noted that the decrease in ALR2 expression in malignant tumors

cannot be considered either as a consequence of a general

dedifferentiation of the tumor or it contributes to the

pathogenesis of this disease by promoting alterations in cell-

cell communication through progressive loss of gap junctions.

20

Together with ALR2, another protein is often correlated with

cancers and this is ALR1 protein and therefore should be

mentioned at this point. This novel human protein that is highly

homologous to ALR2 was identified by Cao et al. [65]. A novel

function of ALR-1 in tumorgenic mammary epithelial cells, that

involves regulating fatty acid synthesis, was reported. These

data suggested that ALR-1 is a novel regulator of the

biosynthesis of fatty acids, which are essential components of

the cell membrane.

Chemical classification of ARIs-

1) Compounds containing five-membered cyclic imides such as

spirohydantoins [66].

2) Carboxylic acid derivatives like alrestatin, tolrestat and

zopolrestat [67, 68]

3) Structurally diverse class

4) ARI from natural sources

5) Dietary sources of ARI

1] Cyclic imides-

Sorbinil (1) was the first cyclic imidine (spirohydantoin)

compound, which inspected extensively on the inhibition of AR

21

enzyme. One of the main adverse effects of sorbinil was

hypersensitivity reaction in the early weeks of therapy, which is

most likely emerged from hydantoin moiety. To solve the

hypersensitivity problem, compounds possessing thiazolidinedione

moiety were introduced as hydantoin bioisosters in which the lack

of hypersensitivity was eliminated. [69]. Compounds derived from

sorbinil are methosorbinil (methyl derivative of sorbinil, M

79175), fidarestat (2) (an amide analog of sorbinil, SNK860), and

minalrestat (3) (2-fluoro, 4-bromo benzyl derivative, ARI 509).

Among the latest sorbinil derivatives, fidarestat shows ten-fold

higher potency than sorbinil having some promising advantages

including normalization of erythrocytic sorbitol contents in

neuropathy patients and showing no significant side effects, even

after a year of continuous administration [70], it is still not

being recognized worldwide as an effective inhibitor in the

treatment of diabetic complications, especially in neuropathy.

Due to the fact that thiazolidinedione (4) bearing compounds have

shown antihyperglycemic efficacy [71], and also considered as a

bioisoster of hydantoin moiety (5), still thiazolidinedione is

favored for the AR inhibition [72]. However, a point should be

22

made about hydantoins, as unacceptable side effects related to

toxicity (skin rash and hypersensitivity or liver toxicity) have

rendered them undesirable as drugs [73].

2] Carboxylic acid derivative-

Compounds, which convey flexible carboxylic acid moiety and have

certain requirements for binding to AR enzyme, are found to be of

a great interest within the structural variations to demonstrate

possible interactions with AR enzyme through inhibition. The main

aspect was the integration of minimal structural requirements

with flexible carboxylic acid moiety, which is believed to hold

an important role in the interaction with AR enzyme, especially

in physiological conditions. Alrestatin (6) can be considered as

a leading structure of carboxylic acidtype of compounds similar

to those sorbinil for cyclic imidines. Therefore, since

alrestatin has shown quite remarkable inhibitory activity, a

number of new developing have been trailed including rhodanine

acetic acid derivatives (9) (ONO-2235, epalrestat) [74],

quinolineacetic acids [75], and phthalazinoacetic acids (10)

(ICI-128,436, ponalrestat, statil) [76]. Epalrestat showed an

antiproliferative and antihypertrophic effects on vascular smooth

23

muscle cells induced by high glucose and suppressed intracellular

NADH/NAD+ elevation and reduced the membrane-bound protein kinase

C activation [77]. Tolrestat was introduced into the market in

1989 but was removed in 1996 due to its low of efficacy. The

exchange of acetic acid moiety with benzyl resulted in a drastic

drop of activity. This may show that the flexible acid moiety

might be placed in a position that could serve the interaction

through the enzyme’s binding site. The inclusion of halogen atoms

into the benzyl ring increased the overall potency either due to

their hydrogen bonding properties or the increasing lipopilicity.

Besides this methoxy group at the same ring also served the raise

in activity. It is reported that these compounds showed better

activity pattern than sorbinil. One of the halogenated benzyl

bearing quinazolidinedione compounds is FK-366 (11) (zenarestat),

which exhibits potent AR inhibitory activity and prevents the

development of diabetic complications.

3] Structurally diverse class of ARI-

other most characteristic chemotypes refer to

tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione derivatives [78], 5-

arylidene- 2,4-thiazolidinedione derivatives [69], N-

24

nitromethylsulfonanilide derivatives [79], sulfonylpyridazinone

derivatives [80], N-(3,5-difluorophenol-4-hydroxyphenyl)

derivatives [81,82] and carboxymethylated pyridoindole

derivatives [83].

i) Tetrahydropyrrolo[1,2-a]pyrazine-1,3-dione Derivatives

Tetrahydropyrrolo-pyrazine derivatives (scaffolds a,b,c) were

evaluated for their ability to inhibit porcine lens ALR2 [78].

The most effective ARI from this series of chemotypes was the

inhibitor ranirestat. A quantitative-structure activity

relationship (QSAR) analysis was conducted by Ko et al. [79] in

order to aid the lead optimization and enhance potency and

deliverability of this series of compounds. For this QSAR study

a model derived from racemic descriptors (RS). A five term

RSequation showed that the hydrophobic character of the benzyl

moiety is the major contributing factor to the ALR2 inhibitory

activity [84].

ii) 5-arylidene-2,4-thiazolidinedione Derivatives

This series of compounds involved 5-arylidene-2,4-

thiazolidinediones with various substitution patterns on the

benzylidene moiety. The most active ARI with substitution R-

25

CH=NC6H4OH and R1- H, exerted significant inhibitory activity

(IC50=1.86μM), lying in the same range of sorbinil. In another

report, a SAR analysis [85] resulted in significant information

for 5-arylidene-2,4-thiazolidinediones, acting as efficient

ARIs. It was shown that the introduction of an acetic chain (R1-

CH2COOH) on N-3 of the thiazolinidione ring led to a marked

increase in inhibitory potency, while the presence of an

additional aromatic ring on the 5-benzylidene group increased

the ALR2 inhibitory activity. A reported quantitative structure-

activity relationship (QSAR) study [86] was contacted and from a

multivariant regression it was indicated that substituents, such

as 3- CH3; 3-OC6H5; 3-OCH3; 3-CF3; 4-OCH3; 4-CF3; 4-CH2COOCH3 or

CH2COOH, have poor contribution to the ALR2 inhibitory activity,

which was further supported by the high standard error of the

substituent coefficients in the equation. It was also suggested

that the binding of ARIs with ALR2 was accomplished by means of

a possible hydrogen bond interaction between the acetic acid

moiety of the side chain of thiazolidinediones and the polar

region of the ALR2 active site. The 3-position of the phenyl

26

ring depicted the hydrophobic interaction of the substituted

moiety and the lipophilic pocket of ALR2.

iii) N-nitromethylsulfonanilide Derivatives

A SAR analysis demonstrated that all of the compounds with a

methyl moiety substituted on the nitrogen atom which bears the

nitro methyl sulfonyl group, exhibited better inhibition activity

than the respective non-methyl substituted ones. Replacement of

the methyl group with an ethyl moiety decreased the inhibitory

activity. Similar results were observed when bulky substituents

were substituted on the benzene ring. The bulky subsituents are

interfering with the H-bond interactions between the

nitromethylsulfonyl moiety and proton donor moieties of the

enzyme.

iv) Sulfonylpyridazinones Derivatives

A SAR analysis for scaffold (f), showed that electron-withdrawing

(-F and -Cl) substituents that are reasonably lipophilic gave

potent compounds both in vitro and in vivo. Electron-releasing

substituents (-OCH3 and -CH3) and bulky groups, especially at the

2-position, had unfavorable effect on in vitro potency. Increasing

the length of the linker by one methylene group as in scaffold

27

(g), as well as several halogen-substituted compounds were found

to be more potent in vitro than the best inhibitors in the phenyl

series but less potent in vivo. As regards scaffold (h), the most

potent inhibitors were the ones with a benzofuran moiety.

v) Carboxymethylated Pyridoindole Derivatives

Carboxymethylated tetrahydropyridoindoles and

hexahydropyridoindoles (scaffolds i and l respectively),

structurally based on the antioxidant drug stobadine were

presented as novel zwitterionic ARIs. It was found that the

tetrahydropyridoindole derivatives were more potent ARIs in

comparison to the respective hexahydropyridoindole derivatives.

4] ARI from the natural sources-

Different variety of structurally diverse compounds has been

identified so far from terrestrial, marine and microorganism as

potent in vitro ARIs. ARIs from natural sources are usually

involved, the flavonoids and vitamin C [87] also series of

alkaloids including nandazurine, aporphine, benzylisoquinoline ,

papaverine , berberine [88] have been tested as inhibitors of AR.

28

Also some dietary sources were studied for AR inhibitory activity

and prominent inhibitory activity was found in spinach, cumin,

fennel, lemon, basil and black pepper [90].

Conclusion-

AR is enzyme that has proved its involvement in different

condition like inflammation, asthma, uvitis, cancer and number of

diabetic complications. Also these disease conditions have needs

continuously different new approaches for their treatment. The

enzyme has well studied and has gained a great deal of attention

in last few years. Some major clues about the structure of enzyme

results in development of new effective ARIs. Some of them are in

clinical development. Variety of chemical classes has been

explored as ARIs and used in number of above mentioned diseased

conditions. Some more insight on the structure is needed so that

new molecules with specific inhibitory activity can be developed.

The utility of some of the ARIs in diabetic complications is well29

established with some molecules in clinical development. However

its use in non-diabetic complications needs to be explored.

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Figure 1

52

53

Table 1

Drug under clinical development* -

Sr

.n

o.

Name of

drugSponsor Condition

Status (Phase

in clinical

trial)01 Ranirestat Dainippon

Sumitomo Pharma

DiabeticNeuropathy

Completed

(Phase III )02 Sorbinil National Eye

Institute

Diabetic

retinopathy

Diabetes

mellitus

Completed

(Phase III)

03 Vitamin C Washington State

University

Diabetic

Neuropathies

Completed

(Phase I)

* The data is taken from www.clinicaltrials.gov

54