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Section Editors:

Introduction

follows elevated blood lipids and ectopic deposition of fat

Diacylglycerol O-acyltransferase (DGAT)

Drug Discovery Today: Therapeutic Strategies Vol. 4, No. 2 2007

ham

eObesity poses amajor public health problem in industrialized

as well as in developing countries. Current estimates from the

World Health Organization indicate that worldwide 1.6 bil-

lion adults are overweight (BMI 25) and 400 million areobese (BMI 30). The excess body fat mass predisposes obeseindividuals to the development of insulin resistance and

metabolic syndrome. The metabolic dysregulation that

DGAT also known as diglyceride acyltransferase is a key

enzyme in triglyceride synthesis, catalyzing the final and

rate-limiting step in triglyceride synthesis using 1,2-diacyl-

glycerol (DAG) and long chain fatty acyl CoA as substrates

(Fig. 1). Thus, DGAT plays an essential role in themetabolism

of cellular diacylglycerol and is critically important for trigly-

ceride production and energy storage homeostasis [1].

In mammals, two separate genes encode for DGAT activity

and are designated DGAT1 [2] and DGAT2 [3]. Although both*Corresponding author: S.J. Wertheimer (Stanley.Wertheimer@roche.com)

1740-6773/$ 2007 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2007.10.002 129results in excess adipose mass that predisposes indivi-

duals to insulin resistance and type 2 diabetes. In this

review, we discuss enzymatic regulators of triglyceride

synthesis and lipolysis that may contribute to energy

balance and as such, constitute key drug targets to

treat obesity, insulin resistance and other components

of metabolic syndrome. Furthermore, we review the

published literature on the development of selective

SCD1, DGAT1 and HSL inhibitors as therapeutic stra-

tegies in light of their emerging role as anti-diabesity

drugs.

leads to comorbidities such as type 2 diabetes, coronary heart

disease and hypertension. There is an urgent need to treat

these patients with effective medications to stem the alarm-

ing rise in the numbers of obese and diabetic individuals.

In this report, we integrate recent developments in our

understanding of some of these lipid metabolic enzymes,

namely DGAT1, HSL and SCD1, from genetic, biochemical

and pharmacological studies in animals, and assess their

potential as promising anti-diabesity drugs (Table 1). These

potential drug targets are not yet validated in humans, and

early candidates remain in preclinical and initial clinical

stages of drug development.Fatty acid modulatotreatment of diabesStanley J. Wertheimer1,*, David Bolin2,

Karin Conde-Knape1, Charles Belunis2,

Rebecca Taub1, Cristina M. Rondinone11Department of Metabolic Diseases, Hoffmann-La Roche, Nutley, NJ 07110, U2Department of Discovery Chemistry and Discovery Technologies, Hoffmann-

Body weight is determined by the net difference in

calorie consumption and energy expenditure. The bal-

ance between triglyceride biosynthesis and breakdown

processes in the body determines the amount of total

fat mass in an individual. Positive energy balanceRamakanth Sarabu and Jefferson W. Tilley Roche ResearchCenter, Nutley, NJ 07110, USATHERAPEUTICSTRATEGIES

DRUG DISCOVERY

TODAY

Editors-in-Chief

Raymond Baker formerly University of Sout

Eliot Ohlstein GlaxoSmithKline, USA

Metabolic/endocrine systs for thetyawn Erickson2,

nish Konkar1,

oche, Nutley, NJ 07110, USA

pton, UK and Merck Sharp & Dohme, UK

m

Drug Discovery Today: Therapeutic Strategies | Metabolic/endocrine system Vol. 4, No. 2 2007

atm

L

d

P

P

P

P

P

PTable 1. Comparison of lipid metabolizing targets in the tre

Pros Cons

HSL Inhibition will decrease plasma

levels of free fatty acids, leading

to increased insulin sensitivity

Multiple lipases have been

discovered, suggesting

redundancy in lipolysis

SCD Inhibition will lead to leanness,

increased energy expenditure,

improved glucose tolerance

and enhanced insulin sensitivity

SCD-1 inhibition in skin and

Meibomian gland poses a

safety concern.

Strong proof of concept

from animal models

Selectivity over other SCD5

isozyme is likely to be difficult.enzymes utilize the same substrates, there is no sequence

homology between the DGAT1 and DGAT2 genes. In addi-

tion, both enzymes are widely expressed; however, some

differences exist in the relative abundance of expression in

various tissues.

Both DGAT enzymes have specificity for sn-1,2 diacylgly-

cerols andwill accept awide variety of fatty acyl chain lengths

[4]. DGAT activity levels increase in fat cells as they differ-

entiate in vitro and recent evidence suggests that DGAT

expression may be regulated in adipose tissue post-transcrip-

tionally [5]. DGAT activity is primarily expressed in the

endoplasmic reticulum [6]. In hepatocytes, DGAT activity

has been shown to be expressed on both the cytosolic and

luminal surfaces of the endoplasmic reticular membrane [7].

In the liver, the regulation of triglyceride synthesis and

partitioning between retention as cytosolic droplets and

Increased BMI correlates with

increased SCD1 expression

in humans

Role of SCD5 isozyme is

unknown

P

c

t

S

DGAT Inhibition will lead to body weight

loss, improved insulin sensitivity,

beneficial lipid effects

Conflicting data regarding

target organ for therapeutic

intervention

P

B

b

is

p

P

P

P

P

P

P

130 www.drugdiscoverytoday.coment of diabesity

atest

evelopments

Companies pursuing

this target

Refs

reclinical Sanofi-Aventis WO2006074957

re-clinical Novo Nordisk WO2006087308

re-clinical Aventis WO2005073199

re-clinical Alteon WO0027388

re-clinical Xenon

Pharmaceuticals

US2005011925

WO2005011654

WO2005011655

WO2005011656

WO2005011657

WO2006125181

Others

re-clinical Merck-Frosst WO2006130986

WO2007009236secretion, is of primary importance in determining the rate

of VLDL production [8].

The overall effect of modulating DGAT expression in vivo

on net energy expenditure, triglyceride and DAG levels, and

insulin resistance could not be predicted. Several animal

models with altered DGAT expression indicate that DGAT

enzymes have key regulatory roles in energy, glucose and

lipid homeostasis. DGAT1 knockout animals (Dgat1/mice), although unable to express a functional DGAT1

enzyme, are viable and continue to synthesize triglycerides

[9]. This would suggest that other enzymes contribute to

triglyceride synthesis, such as DGAT2. Dgat1/ mice havelower tissue triglyceride levels, reduced rates of triglyceride

absorption, and improved glucosemetabolism in comparison

to wild-type mice [9]. Dgat1/ mice are resistant to diet-induced obesity and remain lean because of increased energy

re-clinical. Potent

ompounds

hat recapitulated

CD1/ in vivo.

Abbott Laboratories Abstracts of Papers,

233rd ACS National

Meeting, Chicago, IL,

United States, March 2529,

2007 (2007), MEDI-383

MEDI-382

MEDI-381

MEDI-232

re-clinical Astra-Zeneca WO2005044250

AY744113 (licensed

y Pfizer from Bayer)

reported to be in

hase I trials

Bayer/Pfizer WO2006064189

WO2006134317

WO2004100881

WO2006044775

re-clinical Isis US20040185559

WO2004094618

re-clinical Otsuka JP 2004676351

Sankyo WO2006004200

re-clinical Takeda WO2006082952

re-clinical Japan WO 2004047755

re-clinical Tobacco/Tularik/

Amgen

WO2005013907

re-clinical

Vol. 4, No. 2 2007 Drug Discovery Today: Therapeutic Strategies | Metabolic/endocrine system

gic

co

nati

str

to T

yl tr

orm

teinexpenditure and increased sensitivity to insulin and leptin

[10,11].

Figure 1. Pathways of lipid mobilization and potential targets for pharmacolo

adipose tissue and points of interdiction are outlined. Hepatic SCD activity

participates in the synthesis of TAG, through successive acylation steps, culmi

resulting TAG is then packaged into a VLDL molecule, secreted into the blood

then taken up by adipose tissue. These fatty acids are then re-esterified in

primarily by HSL. Stearoyl-CoA desaturase (SCD), glycerol-3-phosphate-ac

diacylglycerol acyltransferase (DGAT), phosphatidate phosphatase (PPH), h

triglyceride lipase (ATGL), lipoprotein lipase (LPL), very low density lipopopro

(TAG) diacylglycerol (DAG), monoacylglycerol (MAG).Mice lacking DGAT2 (Dgat2/) activity were found to belipopenic and die shortly following birth, partly because of

impaired permeability barrier function in the skin [12].

Knockdown of DGAT2 message in liver and adipose of obese

mice using antisense RNA reduced hepatic triglyceride con-

tent and improved hepatic steatosis. However, no significant

changes in bodyweight, adiposity, metabolic rate and insulin

sensitivity were observed [13]. Further, no changes in skin

microstructure were observed. These findings suggest that

inhibitors of DGAT2 may be beneficial for the treatment of

hepatic steatosis and hyperlipidemia, but have limited use-

fulness in treating obesity.

Overexpression studies of DGAT1 and DGAT2 have been

performed in an effort to further understand the roles of these

enzymes in tissues that synthesize triglycerides, such as liver

and adipose. Adipose specific overexpression of DGAT1 in

mice leads to greater total fat pad weight as compared to

control animals even on a normal chow diet [14]. Further-

more, when fed a high fat diet these animals became 20%more obese compared to the control animals. In another

example, liver DGAT1 and DGAT2 overexpressing mice were

created via adenoviral expression of DGAT1 and DGAT2

genes, respectively [15]. Mice with elevated liver DGAT1

displayed increased VLDL secretion and increased gonadal

fat. On the other hand, mice with elevated liver DGAT2 had

increased liver triglyceride levels, an unaffected VLDL secre-tion rate and no increase in fat pad mass. These data suggest

that the DGAT1, rather than DGAT2, is a contributor to the

al intervention. The major pathways of lipogenesis and lipolysis in liver and

nverts stearoyl-CoA into oleoyl-CoA, which as an acyl-CoA molecule

ng in the terminal step in triacylglycerol synthesis, catalyzed by DGAT. The

eam where it is subsequently hydrolyzed, releasing its fatty acids, which are

AG, and upon hormonal stimulation (see text) undergo lipolysis driven

ansferase (GPAT), lysophosphatidic acid acyl transferase (LPAAT),

one-sensitive lipase (HSL), monoglyceride lipase (MGL), adipose tissue

, (VLDL), low density lipoprotein, (LDL), free fatty acid (FFA), triglycerideobese phenotype.

The knowledge gained from the characterization of mice

lacking or overexpressing DGAT1 has prompted the search

for small molecule inhibitors of DGAT1 enzyme as treatment

for obesity and diabetes (Fig. 2). A recent abstract [16]

reported the identification of a potent DGAT1-specific inhi-

bitor. Furthermore, there have been several recent patents

from Bayer describing their DGAT1 inhibitors. In fact, one

DGAT1 inhibitor, BAY74-4113 (licensed by Pfizer from Bayer)

is reported to be in phase I trials. Finally, antisense oligonu-

cleotides [17] and siRNA [18] have also been demonstrated to

decrease DGAT1 activity and can potentially serve as ther-

apeutic agents.

Stearoyl-CoA desaturase (SCD)

SCD catalyzes the rate-limiting step in the biosynthesis of

monounsaturated fatty acids from saturated fatty acids

(Fig. 1). This microsomal enzyme introduces a double bond

at theD9-position of palmitoyl- or stearoyl-CoA, the preferred

substrates, to form palmitoleoyl- and oleoyl-CoA, respec-

tively [19]. Palmitoleic and oleic acid are the most abundant

monounsaturated fatty acids present in membrane phospho-

lipids, triglycerides, wax esters and cholesterol esters. Mono-

unsaturated fatty acids play an important role in apoptosis,

signal transduction, cellular differentiation and skeletal mus-

cle insulin resistance [20].

www.drugdiscoverytoday.com 131

Drug Discovery Today: Therapeutic Strategies | Metabolic/endocrine system Vol. 4, No. 2 2007Four isoforms of SCD have been identified and cloned in

mice. Of the four, SCD1 is the most widely expressed and has

been extensively characterized [23]. In humans, two SCD

isoforms, SCD1 and SCD5 have been cloned and show 85%

and 65% identity to murine SCD1 [2123].

The relationship between the level of SCD enzyme activity

in lipid metabolism and insulin resistance has been described

in several clinical studies. Studies in humans indicate that a

high level of saturated fatty acids or a low level of unsaturated

fatty acids in plasma may predict the development of type 2

Figure 2. Representative compounds for each target.

132 www.drugdiscoverytoday.comdiabetes but both the substrates and the products (saturated

and monounsaturated fatty acids) of SCD1 are negatively

correlated with type 2 diabetes [24]. SCD activity, inferred

oleic as ratio of to stearic acid, has been negatively correlated

with insulin resistance in patients with impaired glucose

tolerance [25]. Moreover, elevated SCD activity in skeletal

muscle is positively associated with increased percentage of

body weight in humans [26] and there is a strong correlation

between elevated SCD activity and plasma triglyceride levels

in humans [27,28].

Vol. 4, No. 2 2007 Drug Discovery Today: Therapeutic Strategies | Metabolic/endocrine systemThe role of SCD in regulating lipid metabolism has been

examined critically in rodent models of obesity and diabetes.

Studies in rodents indicate that down regulation of SCD1 is

an important component of leptins metabolic actions [29].

In addition, SCD1 functions as an intermediary in the

increase in lipogenic genes observed either upon high-fat

feeding or after LXR agonist treatment [30]. A recent study

examined the effect of infusing glucose into the rodent brain.

Glucose sensing led to a decrease in liver SCD1 activity and a

resultant decrease in plasma triglycerides [31].

Studies involving targeted disruption of SCD1 gene expres-

sion either by genetic knockout (Scd1/) or by antisenseoligonucleotide (ASO) inhibition inmice indicate that Scd1/ mice are resistant to diet-induced obesity, have reducedbody fat and leptin levels, and show increased insulin sensi-

tivity and energy expenditure [29,3234]. In these animals,

the expression of several genes involved in lipid oxidation is

increased, while those of lipid synthesis are decreased. How-

ever the interpretation of these studies is hampered by the

fact that total spacing body knockout of SCD1 leads to serious

eye and skin defects, the latter contributes to increased

energy expenditure via body temperature dysregulation

[35]. Tissue specific deficiency using a sequence specific

ASO for 5 days to lower hepatic SCD1 expression in rodents

fed a high fat diet was able to reverse hepatic insulin resis-

tance as well as decrease gluconeogenesis, resulting in lower

glucose production [34]. These changes in hepatic glucose

production were associated with increased hepatic AKT phos-

phorylation and decreased Glc-6-Pase and PEPCK expression.

While the reduction in SCD1 activity resulted in the expected

decrease in the levels of circulating triglycerides, an increase

in the concentration of liver triglycerides was observed. These

results contrast with those observed in Scd1/ mice and inmice subjected to 10 week ASO treatment that led to reduced

Scd1 mRNA and or enzyme activity in mouse liver, WAT and

BAT [33]. In these animals there was a decrease in de novo fatty

acid synthesis and steatosis in the liver of the ASO-treated

animals, together with significant reduction in body weight

gain and significant increases in oxygen consumption and

resting metabolic rate. The mechanism by which SCD inhibi-

tion leads to reduction of triglyceride synthesis and increased

energy expenditure is not yet fully elucidated.

Based on results seen in the aforementioned rodentmodels

and clinical studies, pharmaceutical companies are seeking to

develop inhibitors of SCD1 as therapy for dyslipidemia, insu-

lin resistance and obesity. Given the adverse skin and eye

findings with total SCD1 deficiency, it may be important to

design small molecule SCD1 inhibitors with limited tissue

distribution. At present, only three companies have described

their work on SCD1 inhibitors: Xenon Pharmaceuticals,

Merck Frosst and Abbott Labs (Fig. 2). The Xenon [36] and

Merck Frosst [37] compounds were disclosed in publishedpatent applications and the Abbott Labs work was presentedat a recent American Chemical Society conference [38]. All

three groups describe compounds very similar to those first

described by Xenon. In fact, Abbott acknowledges using the

Xenon compounds as a starting point for its scaffold hop-

ping/lead optimization effort. Abbott is alone in describing

in vivo results and report mice treated with their inhibitors

exhibited a complete recapitulation of the Scd1/ pheno-types, including the clinically relevant side effects [39], pre-

sumably skin and glandular pathologies.

Hormone sensitive lipase (HSL)

The main physiological role of white adipose tissue (WAT) is

to supply energy when it is needed by other tissues. The most

important enzyme inWAT believed responsible for hormone

regulated hydrolysis of triglyceride is HSL. This enzyme is also

present in the liver, skeletal muscle, pancreas and adrenal

glands. In the basal state, it has minimal activity against its

substrate. Stimulation of adipocytes by hormones activates

protein kinase A resulting in the phosphorylation of HSL and

the lipid droplet coating protein perilipin. Phosphorylation

of perilipin leads to its removal from the lipid droplet and

migration of phosphorylated HSL from the cytosol to the

lipid droplet resulting in hydrolysis of triglycerides [40].

Obese or insulin resistant subjects have increased visceral

adipose tissue depots. These depots contain elevated levels of

HSLprotein [41] andexhibitenhanced lipolytic activityas they

are resistant to the insulin-mediated suppression of lipolysis.

This results in increased plasma levels of free fatty acids (FFA),

which further exacerbates insulin resistance because of the

accumulation of triglycerides in tissues other than WAT such

as liver, pancreas andmuscle. The ectopic deposition of trigly-

cerides results in pathological effects such as increased glucose

production in the liver, decreased insulin secretion from the

pancreas, and reduced glucose uptake and fatty acid oxidation

in skeletal muscle. Thus, the elevated plasma levels of FFA

because of increased HSL activity contributes to and worsens

insulin resistance in obese and type 2 diabetic individuals.

In order to gain insight into the role of HSL, several

laboratories have generated mice lacking functional HSL

(HSl/) [42]. Interestingly, adipose tissue from (HSl/)animals retained 30% of their basal lipolytic activity, suggest-

ing that there are additional lipases, which contribute to

adipose tissue lipolysis. Subsequent work has identified a

novel adipose tissue lipase, referred to as adipose tissue tri-

glyceride lipase or ATGL [43]. Together, HSL and ATGL con-

stitute the majority of lipolytic activity within WAT.

Interestingly, all the (HSL/) mouse models share the fol-lowing common characteristics including decreased plasma

FFA and triglyceride levels, resistance toweight gainwhen fed

a high fat diet and decreasedWAT. In addition, one group has

observed that the knockout of HSL led to reduced hepatic

triglyceride levels and increased hepatic insulin sensitivity[44]. Taken together, these data suggest that pharmacological

www.drugdiscoverytoday.com 133

Drug Discovery Today: Therapeutic Strategies | Metabolic/endocrine system Vol. 4, No. 2 2007inhibition of HSL might improve insulin resistance and

reduce WAT tissue mass.

The importance of HSL to hormone-stimulated triglyceride

hydrolysis has spurred efforts to identify inhibitors of this

enzyme (Fig. 2). For example, researchers at Bayer identified

the compound 4-isopropyl-3-methyl-2-{[3S]-3-methylpiper-

dine-1-yl} carbonyl}isoxazole-5(2H) as a potent and selective

inhibitor of HSL [45] with no inhibitory activity towards

mechanistically related lipases such as pancreatic lipase,

hepatic lipase, lipoprotein lipase and acetylcholinesterase.

In a recent publication from the same group [46], the inhi-

bitor selectivity was further characterized and demonstrated

to have no inhibitory activity towards ATGL. The compound

was also shown to reversibly inhibit HSL. In addition, inhibi-

tion of HSL was demonstrated to have no effect on insulin

secretion in rat islets. Moreover, the compound was shown to

acutely reduce FFA levels in rats, dogs and mice.

Conclusion

The ever escalating global increase in metabolic diseases

including obesity and type 2 diabetes has prompted much

research into the underlying biochemistry of lipid metaboliz-

ing enzymes and their associated metabolic pathways of

synthesis and degradation. The enzymes described in this

review represent different points for potential pharmacolo-

gical intervention in normalizing lipid flux. Thus far none of

these targets or pathways has been validated in human

clinical studies with drug candidates. Restoring the exagger-

ated plasma FFA and triglyceride levels through inhibition of

HSL would reduce the accumulation of triglycerides in tissues

other than WAT, such as liver, muscle and the pancreas

resulting in decreased hepatic glucose output, increasedmus-

cle fatty acid oxidation and improving b-cell function. Alter-

natively, regaining metabolic control of lipid synthesis via

inhibition of SCD1 or DGAT1 would lead to decreased trigly-

ceride levels in the aforementioned tissues, representing an

additional approaches to enhance insulin sensitivity in these

metabolically active tissues. Continued research on these

promising targets will likely lead to improved small molecule

inhibitors to treat obesity, insulin resistance and diabetes.

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Vol. 4, No. 2 2007 Drug Discovery Today: Therapeutic Strategies | Metabolic/endocrine systemwww.drugdiscoverytoday.com 135

Fatty acid modulators for the treatment of diabesityIntroductionDiacylglycerol O-acyltransferase (DGAT)

Stearoyl-CoA desaturase (SCD)Hormone sensitive lipase (HSL)ConclusionReferences