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aMedicinal Chemistry Laboratory, Research

Warangal 506 006, Andhra Pradesh, India

Tel: +91 8008098787bDiabetes and Aging Research Division, D

College of Pharmacy, Kakatiya University, WcDr. Reddy's Institute of Life Sciences, Unive

Hyderabad 500 046, India. E-mail: manoj

1500dThe University of Queensland, School of Ph

† Electronic supplementary information (Espectral data for all new compounds, resu10.1039/c3md00377a

Cite this: DOI: 10.1039/c3md00377a

Received 9th December 2013Accepted 23rd January 2014

DOI: 10.1039/c3md00377a

www.rsc.org/medchemcomm

This journal is © The Royal Society of

Construction of phenoxazine rings containing nitroand sulfonic acid groups leading to phenoxazine-3-sulfonamide derivatives: their evaluation as noveland potential insulin secretagogues†

Seelam Venkata Reddy,a Gangula Mohan Rao,a Baru Vijaya Kumar,*a

Koppela Naresh Reddy,b Konda Sravya,b Puchchakayala Goverdhan,b

Vandana Rathore,c Girdhar Singh Deorad and Manojit Pal*c

A series of N-(alkyl/aryl/heteroaryl)-1-nitro-10H-phenoxazine-3-sulfonamides was designed, synthesized

and evaluated for its hypoglycemic, hyperglycemic and oral anti-diabetic activities. These compounds

were prepared via the construction of a phenoxazine ring containing nitro and sulfonic acid groups in a

single step followed by further transformations. One of these compounds exhibited promising anti-

diabetic activities comparable to glibenclamide and increased serum insulin levels indicating its potential

as a novel insulin secretagogue.

Type 2 Diabetes Mellitus (T2-DM) is effectively controlled by anapproach which is polypharmaceutical1 in nature, targeting theeffects of insulin sensitivity and related dyslipidemia andtherefore cardiovascular diseases. However, this approach isnot encouraged due to its potential additional risks.2 It istherefore necessary to search for newer agents to circumvent therisks involved in combination therapy. Accordingly, an attemptwas made to design a unique pan agonist3a of PPARs (peroxi-some proliferator-activated receptors) that has a bulkier hetero-cyclic scaffold with a sulfonamide side chain possessing thenecessary geometry and electrostatics which are complemen-tary to PPARs. Notably, PPAR a, g and d have been the targets ofintense preclinical research to treat dyslipidemia.3b The inves-tigation revealed that these three receptors are closely relatedand the design of a molecule which competently activates themis an intellectual challenge.4 Indeglitazar (A, Fig 1), a sulfon-amide based PPAR pan-active anti-diabetic agent, has beendiscovered using a process that couples low-affinity biochemicalscreening with high-throughput co-crystallography.5 The

Centre, C.K.M. Arts and Science College,

. E-mail: baruvijayakumar@yahoo.com;

epartment of pharmacology, Vaagdevi

arangal 506 006, Andhra Pradesh, India

rsity of Hyderabad Campus, Gachibowli,

itpal@rediffmail.com; Tel: +91 40 6657

armacy, Brisbane, Qld 4072, Australia

SI) available: Experimental procedures,lts of pharmacological studies. See DOI:

Chemistry 2014

phenoxazine moiety on the other hand has been explored in thediscovery and development of a dual PPAR agonist, DRF 2725,that has shown potent antihyperglycemic and lipid modulatingproperties.6 This, and our continued interest in novel anti-dia-betic agents,7–10 prompted us to design a series of new sulfon-amides, represented by B (Fig. 1), bearing phenoxazinemoieties. The key structural features of A were partly main-tained in B with the hope that the resulting analogues wouldshow in vivo pharmacological properties similar to A. Moreover,some of the structural features of glibenclamide (C, Fig. 1), awell known anti-diabetic drug, were also incorporated in B.Introduction of the R group into the sulfonamide moiety of Ballowed the generation of a diverse library of small moleculesfor pharmacological studies. Thus a series of sulfonamides,bearing bulky phenoxazine moieties, related to B were preparedand evaluated for hypoglycemic, hyperglycemic and anti-dia-betic activities, body weight changes, serum lipid proles, SGOT(serum glutamic oxaloacetic transaminase) and SGPT (serumglutamic pyruvic transaminase) levels and the histology of thepancreas. To the best of our knowledge evaluation of this classof molecules as potential anti-diabetic agents has not beenpreviously reported. Herein we report our preliminary results ofthis study.

Several syntheses11–15 of substituted phenoxazines have beenattempted but the incorporation of two substituents, such asnitro and sulfonic acid groups, in a single step followed bymodication of these substituents remains unexplored. Arecent report16 shows the synthesis of phenoxazine derivativesstarting from 2-aminophenol and substituted diuorobenzenefollowed by the introduction of a sulfonic acid group at the C-3position of the phenoxazine nucleus D (Fig. 2).

Med. Chem. Commun.

Fig. 1 The design of new molecules, B, based on the known PPARpan-active anti-diabetic agent indeglitazar A and another anti-diabeticdrug glibenclamide C.

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While the synthesis of 1-nitro-10H-phenoxazine-3-sulfonicacid E (Fig. 2) or 2 (Scheme 1) was reported17 by Ullmann et al. in1909, the conversion of the sulfonic acid group to sulfonamideremained a challenge.18,19 However, the use of phosphorusoxychloride in the absence of any solvent afforded the expectedsulfonyl chloride 5 (Scheme 1).20 Thus, the key starting material,i.e. 4-chloro-3,5-dinitrobenzenesulfonic acid (4), was synthe-sized from chlorobenzene (3) according to a reported procedure(Scheme 1).21 Compound 4 was then condensed with 2-amino-phenol (1) to give 1-nitro-10H-phenoxazine-3-sulfonic acid (2)which was converted to the corresponding sulfonyl chloride (5).

Compound 5was then condensed with ammonia20 or variousalkyl/aryl and heteroaryl amines to afford 6a–u.22

All compounds were characterized by IR, NMR and MSspectral data. Compounds 6a (ref. 20) and 6b–u generallyshowed a singlet near d 9.7 (NH group) and two doublets near d7.9 and 7.0 ppm (with J¼ 2.0 Hz) due to the C-2 and C-4 protonsof phenoxazine, respectively, in their 1H-NMR spectra. Theremaining protons of phenoxazine (H8, H7, H6 and H9)appeared as multiplets in the d 7.2–7.1 and 6.8–6.7 ppm regions.

The hypoglycemic activities of all synthesized compoundswere initially evaluated at a dose of 20 mg kg�1. Glibenclamideis oen used as a standard anti-diabetic drug in streptozotocin-induced moderate diabetes to compare the efficacy of a varietyof hypoglycemic agents.23 The effect of the test compounds i.e.6a–u on fasting blood sugar levels was assessed in normal ratsat various time intervals as shown in Table 1. Some of thecompounds caused signicant maximum reductions in bloodglucose levels in normal rats when tested at 10 mg kg�1 alongwith 10 mg kg�1 of glibenclamide aer 2 h of treatment e.g. 6a(�35%), 6m (�54%), 6o (�47%), 6p (�24%), 6r (�27%), 6s(�25%) 6t (�28%) and 6u (�32%). The compounds thatproduced encouraging reductions in blood glucose levels aer 6h are 6a (�50%), 6b (�40%), 6d (�25%), 6m (�43%), 6n(�44%), 6o (�12%), 6r (�21%) and 6u (�30%). Some of these

Fig. 2 Phenoxazine derivatives D and E.

Med. Chem. Commun.

promising and representative compounds e.g. 6a, 6b, 6d, 6g, 6l,6m, 6o and 6s were taken for further screening e.g. intraperi-toneal glucose tolerance test (IPGTT).

When the selected compounds were administered to glucoseloaded normal rats which had fasted for 18 h, hypoglycemiceffects were observed aer 30 min as shown in Table 2. In thecases of compounds 6g, 6l and 6m, the decline in blood sugarlevels reached a maximum at 90 min. Nevertheless, compounds6m and 6g were evaluated further for their anti diabetic effects.A sub acute study was also performed on 6m. The differenceobserved between the initial and nal fasting plasma glucoselevels of different groups under investigation revealed a signif-icant elevation in blood glucose in the diabetic control groupcompared with normal animals at 0 days as shown in Table 3and at the end of the 14-day experimental period as shown inTable 4. These results indicated the promising effects ofcompound 6m in maintaining the blood glucose levels instreptozotocin–nicotinamide induced diabetic rats. Adminis-tration of 6m to diabetic rats showed a signicant decrease inthe blood glucose levels. A marked increase in the totalcholesterol and triglyceride levels has been observed inuntreated diabetic rats. Under normal circumstances insulinactivates the enzyme lipoprotein lipase and hydrolyses triglyc-erides. An insulin deciency results in failure to activate the

Scheme 1 Reagents and conditions: (a) oleum, conc. H2SO4, KNO3,130 �C, 2 h; (b) 2-aminophenol (1), NaOH, ethanol, reflux, 4 h; (c)POCl3, reflux, 3 h; (d) aqueous NH3, THF, 0 �C, 30 min; (e) aryl/alkyl/heteroaryl amines, chloroform, Et3N, 60 �C, 30 min.

This journal is © The Royal Society of Chemistry 2014

Table 1 Hypoglycemic effects of the test compounds 6a

Test groupDose (mg kg�1 ofbody weight (b. wt))

Blood glucose (mg dl�1)

Pre treatmentPost treatment

0 h 2 h 4 h 6 h

Control 0.5% gum acacia 102.23 � 4.03 101.03 � 1.93 97.13 � 2.89 101.01 � 1.60Glibenclamide 10 98.13 � 7.23 90.2 � 4.50* 63.73 � 11.50** 69.01 � 5.93***6a 10 91.14 � 42.84 65.62 � 40.45** 69.79 � 33.20* 51.04 � 19.90***6b 10 89.58 � 24.50 106.25 � 16.88 91.66 � 27.36 60.93 � 16.62***6c 10 80.20 � 20.50 86.45 � 25.89 114.06 � 18.19 84.37 � 20.056d 10 115.62 � 4.41 116.66 � 7.03 120.31 � 16.50 74.47 � 17.27**6e 10 110.93 � 7.05 102.60 � 9.14 100 � 7.90 118.22 � 3.076f 10 113.54 � 8.30 102.60 � 5.38 102.08 � 4.70 85.93 � 9.006g 10 106.25 � 17.56 95.31 � 9.42* 85.42 � 14.87** 89.58 � 9.19**6h 10 129.17 � 13.35 122.92 � 20.02 113.54 � 17.64 118.75 � 9.686i 10 96.43 � 10.55 93.55 � 7.92 89.88 � 12.94 85.42 � 4.106j 10 99.58 � 10.84 90.22 � 6.78 85.63 � 6.94 90.20 � 7.566k 10 103.79 � 6.04 95.45 � 4.97 87.88 � 4.69 93.94 � 4.696l 10 105.30 � 3.42 96.21 � 3.42* 86.36 � 2.87* 100.76 � 4.466m 10 71.76 � 1.44 46.34 � 4.87*** 44.65 � 3.61*** 66.14 � 4.50**6n 10 72.23 � 6.03 59.35 � 4.50 61.56 � 9.29 65.27 � 3.406o 10 82.11 � 7.07 52.43 � 2.58** 73.33 � 12.81 87.93 � 6.606p 10 102.22 � 5.06 75.48 � 6.68 88.70 � 7.90 98.70 � 4.476q 10 96.38 � 7.95 78.26 � 5.42 77.74 � 11.08 94.28 � 9.756r 10 80.27 � 16.08 72.67 � 20.95 69.35 � 6.74 78.41 � 6.306s 10 95 � 8.48 74.28 � 10.49 86.45 � 9.58 91.74 � 11.466t 10 89.72 � 12.63 71.38 � 8.81 85.0 � 8.18 88.88 � 13.996u 10 73.61 � 6.21 67.5 � 7.12 63.05 � 8.59 69.44 � 4.91

a Values are mean � SD (standard deviation), n ¼ 6 in each group, *p < 0.05, **p < 0.01 and ***p < 0.001 when compared with the vehicle treatedgroup (Dunnett's test).

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enzymes, thereby causing hypertriglyceridemia. The signicantlowering of total cholesterol (Table 5) and triglyceride (Table 6)levels observed with compound 6m is a desirable biochemicalstate for the prevention of atherosclerosis and ischemic condi-tions.24 The observed hypolipidemic effect may be caused bydecreased cholesterogenesis and fatty acid synthesis.

It is known that diabetes raises the serum activity levels ofthe liver enzymes AST (aspartate aminotransferase) and ALT

Table 2 Intraperitoneal glucose tolerance test on selected compounds

Test compound Dose (mg kg�1 b. wt)

Blood glucose (mg dl�1)

Before glucoseadministration

Aer gluco

0 min 30 min

Control 0.5% gum acacia 82.21 � 5.58 109.28 � 2Glibenclamide 10 76.75 � 12.02 107.85 � 16a 10 98.50 � 16.87 124.20 � 76b 10 75.70 � 18.79 100.36 � 26d 10 102.33 � 12.69 130.35 � 26g 10 83.57 � 18.44 148.35 � 56l 10 75.94 � 5.52 115.43 � 16m 10 91.89 � 14.17 102.43 � 16o 10 74.55 � 15.03 123.21 � 16s 10 72.33 � 14.22 124.33 � 3

a Values are mean � SD, n ¼ 5 in each group, *p < 0.05, **p < 0.01 and ***

This journal is © The Royal Society of Chemistry 2014

(alanine transaminase). Elevated activities of serum amino-transferases are a common sign of liver and cardiovasculardiseases and are observed more frequently among people withdiabetes than in the general population. Such alterations totransaminase activity in the tissues are explicable causes ofenergy metabolism, as these enzymes play a role in gluconeo-genesis.25 Compound 6m has been found to reverse theincreased SGPT and SGOT activities towards near normality,

a

se administration

60 min 90 min 120 min

0.53 106.07 � 13.98 94.44 � 6.99 101.07 � 8.982.91** 89.0 � 8.07*** 77.5 � 12.66*** 91.78 � 23.33**.74 112.31 � 16.31 105.72 � 29.27 122.85 � 8.313.30 106.23 � 20.93 93.77 � 17.86 76.90 � 3.359.63 96.07 � 7.82 91.42 � 9.31 107.14 � 27.28.02 111.4 � 17.38** 137.5 � 13.71 119.64 � 20.703.42 81.89 � 17.08 80.0 � 22.74 83.89 � 21.111.52** 95.40 � 14.41*** 78.10 � 25.91*** 98.91 � 25.37**6.10 100.44 � 9.79 97.32 � 20.28 100.0 � 19.611.17 96.66 � 10.20 98.0 � 23.13 106.0 � 23.82

p < 0.001 when compared with the vehicle treated group (Dunnett's test).

Med. Chem. Commun.

Table 3 Anti diabetic effect of test compounds N-(4-bromophenyl)-1-nitro-10H-phenoxazine-3-sulfonamide (6g) and N-(4-hydroxyphenyl)-1-nitro-10H-phenoxazine-3-sulfonamide (6m)a

Time (h)

Blood glucose (mg dl�1)

Control(0.5% gum acacia)

Diabetic control(0.5% gum acacia)

Glibenclamide(10 mg kg�1 b. wt)

Compound 6g(10 mg kg�1 b. wt)

Compound 6m(10 mg kg�1 b. wt)

0 98.3 � 6.68 185.5 � 10.04 159.3 � 11.36 183.8 � 7.51 189.2 � 6.511 94.4 � 5.56 180.8 � 10.50 147.2 � 13.75** 165.8 � 18.12 158.6 � 9.98*2 89.7 � 6.10 173.3 � 12.86 101.9 � 7.83*** 145.6 � 13.59** 116.4 � 13.23***4 87.5 � 9.91 171.9 � 7.24 107.5 � 7.32*** 157.5 � 8.59 131.4 � 21.60***6 87.5 � 7.08 172.5 � 8.06 127.2 � 12.29*** 165.6 � 6.31 143.3 � 22.17**8 96.1 � 10.55 178.6 � 9.45 151.9 � 12.17** 172.2 � 5.46 161.4 � 10.08*

a Values are mean � SD, n ¼ 5 in each group, *p < 0.05, **p < 0.01 and ***p < 0.001 when compared with the vehicle treated group (Dunnett's test).

Table 4 Anti diabetic effect of N-(4-hydroxyphenyl)-1-nitro-10H-phenoxazine-3-sulfonamide (6m) on different days (sub acute)a

Time (day)

Blood glucose concentration (mg dl�1)

Control (0.5%gum acacia)

Diabetic control(0.5% gum acacia)

Glibenclamide(10 mg kg�1)

Compound 6m(10 mg kg�1)

0 88.8 � 6.94 173.3 � 12.86 101.9 � 7.83 116.4 � 13.237 90 � 10.27 175.6 � 9.13 93.3 � 8.18*** 165.8 � 18.12***14 86.1 � 5.81 175.8 � 5.06 88.3 � 8.48*** 145.6 � 8.41***

a Values are mean � SD, n ¼ 5 in each group, ***p < 0.0001 when compared with the diabetic control group (Dunnett's test).

Table 5 Total cholesterol levels in diabetic rats and normal rats (sub acute study) treated with compound 6ma

Time (day)

Total cholesterol (mg dl�1)

Control (0.5%gum acacia)

Diabetic control(0.5% gum acacia)

Glibenclamide(10 mg kg�1)

Compound 6m(10 mg kg�1)

0 51.4 � 11.46 110.7 � 16.56 98.5 � 11.46 97.8 � 18.9914 54.2 � 10.83 120.7 � 17.2 57.8 � 6.87*** 59.2 � 8.96***

a Values are mean � SD, n ¼ 5 in each group, ***p < 0.001 when compared with the diabetic control group (Dunnett's test).

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which suggests prevention of cellular and tissue damage underdiabetic conditions as shown in Table 7.

The induction of diabetes with streptozotocin (STZ) is asso-ciated with the characteristic loss of body weight which is due toincreased muscle wasting26 and loss of tissue proteins. Diabeticrats treated with compound 6m showed an increase in body

Table 6 Serum triglyceride levels in diabetic rats and normal rats (sub a

Time (day)

Serum triglyceride (mg dl�1)

Control (0.5%gum acacia)

Diabetic contr(0.5% gum aca

0 60.5 � 15.36 108.1 � 25.2814 61.0 � 11.4 117.3 � 19.64

a Values are mean � SD, n ¼ 5 in each group, ***p < 0.001 when compar

Med. Chem. Commun.

weight compared to the diabetic control (Table 8), suggesting itsprotective effect in controlling muscle wasting, i.e. reversal ofgluconeogenesis, and may also be due to better glycemiccontrol.

It is well established that glibenclamide causes hypogly-cemia by increasing the secretion of insulin from the existing

cute study) treated with compound 6ma

olcia)

Glibenclamide(10 mg kg�1)

Compound 6m(10 mg kg�1)

102.7 � 18.33 101.6 � 13.5961.0 � 7.78*** 63.2 � 11.24***

ed with the diabetic control group (Dunnett's test).

This journal is © The Royal Society of Chemistry 2014

Table 7 SGOT and SGPT levels after 14 days in diabetic rats and normal rats (sub acute study) treated with compound 6ma

Liver transaminase

Serum SGOT, SGPT levels (U dl�1)

Control (0.5%gum acacia)

Diabetic control(0.5% gum acacia)

Glibenclamide(10 mg kg�1)

Compound 6m(10 mg kg�1)

SGOT 41.0 � 4.47 86.0 � 5.47 45.8 � 5.89*** 47.2 � 5.26***SGPT 38.4 � 7.92 87.4 � 10.67 42.0 � 7.51*** 44.8 � 5.84***

a Values are mean � SD, n ¼ 5 in each group, ***p < 0.001 when compared with the diabetic control group (Dunnett's test).

Table 8 Body weights of diabetic rats and normal rats (sub acute study) treated with compound 6ma

Time (day)

Body weight (g)

Control (0.5%gum acacia)

Diabetic control(0.5% gum acacia)

Glibenclamide(10 mg kg�1)

Compound 6m(10 mg kg�1)

0 200 � 25.00 220 � 44.72 212 � 22.95 217 � 28.6214 248 � 17.53** 189 � 36.81 244 � 16.85* 242 � 28.07*

a Values are mean � SD, n ¼ 5 in each group, *p < 0.05, **p < 0.01 when compared with the diabetic control group (Dunnett's test).

Fig. 3 Histology of the pancreas in experimental rats after 14 days oftreatment with 6m (10 mg kg�1). (A) Normal control – presence ofnormal pancreatic islet cells. (B) Diabetic control – degranulated anddilated islet cells. (C) Diabetic + glibenclamide (10 mg kg�1) – granu-lated, absence of dilation and prominent hyperplasticity. (D) Diabetic +6m (10 mg kg�1 b. wt) granulated pancreatic islets, showing prominenthyperplasticity.

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pancreatic b-cells.27 The hypoglycemic effect of 6m is generallydependent upon the degree of b-cell destruction. Treatment ofmoderately diabetic rats with 6m resulted in the stimulationof b-cells of the islets of Langerhans. Histopathological studiesof the pancreas revealed that test compound 6m signicantlyimproved the histological architectures of the islets of Langer-hans (Fig. 3). Groups treated with 6m showed greater isletpersistence and a smaller degree of necrotic changes comparedto the untreated STZ diabetic rats.

To rationalize the anti-diabetic activity of this class ofmolecules we performed in vitro transactivation28 of PPARg with6m and compared it with the known PPARg specic activatorrosiglitazone. PPARs (a group of nuclear receptor proteins thatfunction as transcription factors regulating the expression ofgenes) play essential roles in the regulation of cellular differ-entiation and in the development and metabolism (carbohy-drate, lipid and protein) of higher organisms. PPARg is themolecular target of antidiabetic drugs such as TZDs (thiazoli-dinediones). Compound 6m and rosiglitazone showed 15.48 �1.32 and 18.5� 1.17 [values are expressed as mean� SD (n¼ 4)]fold activation of PPARg respectively when tested at 1.0 mM,indicating that 6m exerts its anti-diabetic effects through ago-nising the nuclear receptor. Since PPARg agonists are known tobe cytotoxic to rat primary hepatocytes in a time and dosedependent manner,29 compound 6m along with rosiglitazonewere tested for cytotoxicity to rat primary hepatocytes. Prelimi-nary data, i.e. IC50 values of 343 mM for 6 h and 274 mM for 16 htreatment in the case of compound 6m and 225 mM for 6 h and165 mM for 16 h treatment in the case of rosiglitazone, indicatedthat 6m may have advantages over rosiglitazone.

In conclusion, we report for the rst time thedesign, synthesis and evaluation of a novel series of N-(alkyl/aryl/heteroaryl)-1-nitro-10H-phenoxazine-3-sulfonamides asinsulin secretagogues. These compounds were prepared from

This journal is © The Royal Society of Chemistry 2014

1-nitro-10H-phenoxazine-3-sulfonic acid via 1-nitro-1H-phe-noxazine-3-sulfonyl chloride and the synthetic method adopteddoes not require the use of any expensive reagents or catalystsand can be used to prepare a library of compounds. All thesynthesized compounds were evaluated for their hypoglycemic,hyperglycemic and oral anti-diabetic activities. Normoglycemicand STZ-nicotinamide induced diabetic rats were treated withthe sulfonamides under investigation at concentrations of10 mg kg�1 of body weight and signicant (p < 0.001) reductions

Med. Chem. Commun.

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in fasting blood glucose levels were observed. In addition,changes in body weight, serum lipid proles, and SGOT andSGPT levels were assessed for 14 days. Signicant results wereobserved in the estimated parameters when comparing thediabetic control and normal animals. Of the 21 compoundsN-(4-hydroxyphenyl)-1-nitro-10H-phenoxazine-3-sulfonamide(6m) exhibited pronounced anti-diabetic activities comparableto glibenclamide. The histology of the pancreas of testcompound 6m substantiated the cytoprotective action of thedrug. Additionally, the increase in serum insulin levels aertreatment with compound 6m proved that the compound actsas an insulin secretagogue. Overall, our research has identied6m as a promising novel non-TZD agent for the potentialtreatment of diabetes.

BVK thanks UGC, New Delhi, India for the Major ResearchProject (F. no. 35-151/2008). The authors thank the Manage-ment of C.K.M arts and Science College and Vaagdevi College ofPharmacy for providing the necessary facilities.

Notes and references

1 R. P. Austin, Diabetes Spectrum, 2006, 19, 13.2 (a) J. L. Evans, J. L. Lin and I. D. Goldne, Curr. Diabetes Rev.,2005, 1, 299; (b) Some of the adverse effects involved in theuse of common agents e.g. insulin and sulfonylureasinclude hypoglycemia and weight gain. Gastointestinaldisturbances are the common side effects associated withthe use of metformin, acarbose and GLP-1 analogues (inaddition to lactic acidosis for acarbose and nausea,abdominal pain and weight loss for GLP-1 analogues). Theuse of TZDs e.g. pio- and rosiglitazone showed weight gain,edema and anemia. However, several TZDs have shown anincreased risk of cardiovascular events (e.g. rosiglitazone)or bladder cancer (e.g. pioglitazone) or drug-inducedhepatitis (e.g. troglitazone) and are either kept underselling restrictions or have been withdrawn from the market.

3 (a) For a review, see: P. L. Feldman, M. H. Lambert andB. R. Henke, Curr. Top. Med. Chem., 2008, 8, 728; (b)T. M. Wilson, P. J. Brown, D. D. Sternbach andB. R. Henke, J. Med. Chem., 2000, 43, 527.

4 R. W. Grant, N. G. Devita, D. E. Singer and J. B. Meigs,Diabetes Care, 2003, 26, 1408.

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