Novel TACE inhibitors in drug discovery: a review of patented compounds

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1. Introduction

2. TACE inhibitors developed

at Schering Corp.

at Wyeth

at Darwin Discovery Ltd

at Bristol-Myers Squibb Co.

6. TACE inhibitors developed at

Pfizer Ltd

at Glaxo Wellcome, Inc.

at Vertex Pharmaceuticals

at Kaken Pharmaceuticals Co.

10. Expert opinion

Review

Novel TACE inhibitors in drugdiscovery: a review of patentedcompoundsPrashant R Murumkar, Shirshendu DasGupta, Sneha R Chandani,Rajani Giridhar & Mange Ram Yadav††The M.S. University of Baroda, Faculty of Technology & Engineering, Department of Pharmacy,

Kalabhavan, Vadodara, 390 001, India

TNF-a converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the

formation of TNF-a from membrane bound TNF-a precursor protein. TNF-ais believed to play pathophysiological roles in inflammation, anorexia,

cachexia, septic shock, viral replication and so on. TNF-a is a key player in

inflammation and joint damage in rheumatoid arthritis. While a variety of

TACE inhibitors have been reported in the literature, a vast majority of

these compounds are peptidic and peptide-like compounds that are

expected to have bioavailability and pharmacokinetic problems, common

to such compounds, limiting their clinical effectiveness. Low molecular mass,

long acting, orally bioavailable inhibitors of TACE are, therefore, highly

desirable for the treatment of potential chronic diseases mentioned above.

A review of patented compounds as TACE inhibitors in drug discovery is

given. A selection of interesting patents recorded from 2001 to 2009 is

presented. Various novel TACE inhibitors developed by different companies

have been discussed.

Keywords: rheumatoid arthritis, TACE inhibitors, TNF-a converting enzyme

Expert Opin. Ther. Patents (2010) 20(1):31-57

1. Introduction

A well-known fact is that overexpression of TNF-a, a 17 kDa pro-inflammatorycytokine, has been directly associated with inflammatory diseases such as rheumatoidarthritis (RA) and Crohn’s disease [1,2]. Reduction of TNF-a levels, through ascavenging mechanism using either antibodies or TNF-a receptor fusion proteins,has been highly effective in controlling the symptoms of these diseases in variousclinical trials [3-5]. TNF-a functioning is targeted at different levels.

TNF-a can be inhibited [6,7] at two stages: i) Inhibition of pro-TNF-a processing:TNF-a is produced in the body from its precursor form, pro-TNF-a, a 26 kDaprecursor protein [8] through a proteolytic process involving mainly the TNF-aconverting enzyme or TACE (ADAM17), which is a member of the zinc-metallo-protease family known as ADAM (a disintegrin and a metalloprotease) [9,10] to theactive and soluble form, s-TNF-a. Inhibition of this enzyme would automaticallyreduce the amount of active TNF-a in the blood. ii) Inhibition of pro-TNF-asynthesis: Inhibition of pro-TNF-a synthesis could be achieved by using NF-kBinhibitors, PDE inhibitors and thalidomide analogues. It has been proved that NF-kBand PDE, especially PDE4, are involved in the production of TNF-a. Thalidomideand its analogues also inhibit TNF-a production in the body by some unknownmechanism [11].

To control the level of TNF-a release, inhibition of TACEactivity has long been considered as a promising way oftreating related inflammatory diseases [12-14] for which oneof the most attractive strategies is the development of lowmolecular mass inhibitors of TACE [15]. The search for potent,selective and orally active TACE inhibitors is a critical area ofresearch. Till date, much effort has been made to developsmall molecules as TACE inhibitors. For the past few years,this laboratory is also engaged in designing and synthesis ofnovel small molecule TACE inhibitors [11,16-19].In this paper, a review of various classes of patented

compounds as novel TACE inhibitors is presented. So far,TACE inhibitors have evolved from research programs for thedevelopment MMP inhibitors. Two of the early studiesshowed that hydroxamate-based broad spectrum MMP inhi-bitors 1 and 2 could also reduce the production of TNF-a byinhibiting TACE [20,21]. Since then, a handful of other MMPinhibitors have also been shown to inhibit TACE, reflectingstructural similarities between the active sites of MMPsand TACE [22].It is expected that small molecule TACE inhibitors would

have the potential for treating a variety of related disease states.Although a number of TACE inhibitors are known, many ofthese molecules are peptidic and peptide-like, which sufferfrom bioavailability and pharmacokinetic problems. Addi-tionally, many of these molecules are non-selective potentinhibitors of MMPs and in particular, MMP-1 inhibitors.Inhibition of MMP-1 (collagenase 1) has been postulated tocause joint pain in clinical trials of MMP inhibitors [23]. Thus,long acting, selective and orally bioavailable non-peptidicTACE inhibitors could be helpful for the clinical controlof a variety of diseases. Several classes of compounds that arenovel and potent TACE inhibitors have been identified inthe last decade. In this paper, a review of novel patentedTACE inhibitors developed by different groups, namely,Shering Corp., Wyeth, Darwin Discovery, Bristol-MyersSquibb Co., Pfizer, Glaxo Wellcome, Vertex and KakenPharmaceuticals have been presented.

2. TACE inhibitors developed at Schering Corp.

Schering Corp., Kenilworth, has patented a series of novelhydantoin derivatives that specifically inhibit TACE [24]. Thedisclosed series contains a number of derivatives with goodTACE inhibitory activity. TACE inhibitory activity (Ki value)of the specified compounds (3 – 8) indicated that compound 4

is a promising candidate having 0.03 nM Ki value.

3. TACE inhibitors developed at Wyeth

Wyeth Holding Corp. has a long-standing research programfor developing novel TACE inhibitors. In 2007, Sandanayakaet al. have patented a series of allenic aryl sulfonamidehydroxamic acids as TACE inhibitors [25]. This series hasbeen tested for inhibition of TACE along with MMP-1, -9and -13 (Table 1). Out of the listed compounds (9 – 16),compound 10 is the most potent inhibitor (IC50 = 36 nM) ofTACE in the series causingMMP-1 (IC50 = 138 nM), MMP-9(IC50 = 3 nM) and MMP-13 (IC50 = 3 nM) inhibition.

In the same year, Levin et al. have described a series ofacetylenic aryl sulfonate hydroxamic acid TACE inhibitors(17 – 21) in which the aryl sulfonate group is para-substitutedwith a methyl substituted butynyl moiety. These compoundshave been claimed to have high to moderate TACE inhibitoryactivity with selectivity over MMP-1 and -13 (Table 1) [26].Compounds 17 and 18 showed good potency against TACE(IC50 = 19 and 13 nM, respectively) but moderate activity wasreported for compound 20.

Acetylenic ortho-sulfonamido bicyclic heteroaryl hydroxa-mic acids (22 – 26) [27] were also shown to have excellentTACE inhibitory activity (Table 1). Compound 23 has potentactivity against TACE (IC50 = 5.9 nM), but low to moderateactivity against MMP-1, -9 and -13 (IC50 = 1911, 244 and150 nM, respectively).

Certain other acetylenic aryl sulfonamide hydroxamic acidderivatives (27 – 40; Table 1) have also been claimed tohave TACE inhibitory activity [28]. Compound 39 with an

Novel TACE inhibitors in drug discovery: a review of patented compounds

32 Expert Opin. Ther. Patents (2010) 20(1)

3(Ki = 0.44 nM)

4(Ki = 0.03 nM)

5(Ki = 0.094 nM)

6(Ki = 0.11 nM)

7(Ki = 0.31 nM)

8(Ki = 0.11 nM)

Murumkar, DasGupta, Chandani, Giridhar & Yadav

Expert Opin. Ther. Patents (2010) 20(1) 33

IC50 value of 6.8 nM for TACE enzyme is the most potentcompound in the series having IC50 values of 3203, 477 and83 nM for MMP-1, -9 and -13, respectively.

Similar type of compounds, that is, acetylenic-a-aminoacid-based sulfonamide hydroxamic acids (41 – 49) have alsobeen reported in 2004 by the same group having TACEinhibitory activity [29]. Compound 49 is the most potentcompound out of this series having an IC50 value of2.4 nM against TACE enzyme.

Nelson et al. from Wyeth has patented a series of ortho-sulfonamido aryl hydroxamic acids as TACE inhibitors [30].Some of the specified compounds (50 – 52) from this serieshave shown IC50 values of 19.9, 15.2 and 21.3 nM,respectively, for TACE.

These compounds have shown high selectivity for TACEvis-a-vis MMP-1 and much poorer activity against MMP-1when compared to MMP-9 and -13.

Most recently, Park et al. have reported a novel series of non-hydroxamate tryptophan sulfonamide derivatives containing abutynyloxyP1¢moietyas inhibitorsofTACE.Theyexploredtheeffect of substitution around indole core on TACE inhibitoryactivity. In this series of compounds, 5-methyl or 5-methoxysubstituents in the indole ring and N-p-methoxybenzyl groupsignificantly increased inhibitory activity by providing hydro-phobic interactions and/or p interactions with neighboringamino-acid residues in the TACE active site. 2-(4-But-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid (53) is found to be the most potentTACE inhibitor with an IC50 value of 80 nM having goodselectivity over MMP-1, -13 and -14 [31,32].

American Home Products Corp. (now Wyeth) has patentedan assortment of compounds (54 – 65) asMMP inhibitors [33-35].These compounds are also claimed to have TACE inhibitoryactivity. Compound 63 possesses good TACE inhibitory activityhaving an IC50 value of 9.7 nM and shows poor to moderateMMP-9 and -13 inhibitory activities (Table 2).

Preparation and use of ortho-sulfonamido heteroarylhydroxamic acids as MMP and TACE inhibitors have beenpatened in 2001 [36]. However, moderate activity has beenreported for the specified compounds 66 and 67 as far asTACE inhibition is concerned (Table 2).

In 2002 and 2003, the same group has patentedsome ortho-sulfonamido bicyclic heteroaryl hydroxamic acids(68 – 70) as MMP and TACE inhibitors [37,38]. One of thetargeted compounds (68) showed IC50 values of 1 nM forMMP-9 and -13 and 24 nM for TACE enzyme.

Acetylenic b-sulfonamido hydroxamic acid derivatives as aTACE and MMP inhibitors [39] were the subject of a patentfromAmericanCynamidCo. Some of the reported compounds(71 – 74) showed good IC50 values (between 15 and 30 nM) forTACE enzyme in comparison to MMP-1, -9 and -13.

Some thiol containing compounds (75 – 77) have also beenreported [40] to have moderate TACE inhibitory activity.Compound 77 has an IC50 value of 263 nM for TACE.

Table 1. In vitro TACE and MMP inhibitory activity.

IC50 (nM)/% inhibition (µM)

TACE MMP-1 MMP-9 MMP-13

(9) 51 2668 36 21

(10) 36 138 3 3

(11) 62 8806 21 25

(12) 48 887 4 6

(13) 116 50 - 4

(14) 71 2353 9 7

(15) 515 675 - 4

(16) 1400 32% (1) - 5

(17) 19 11% (10) - 38% (10)

(18) 13 07% (10) - 56% (10)

(19) 31 11% (10) - 27% (10)

(20) 361 03% (10) - 45% (10)

(21) 67 16% (10) - 64% (10)

(22) 30 988 116 80

(23) 5.9 1911 244 150

(24) 17 875 33 9.2

(25) 14 2333 95 34

(26) 82 956 - 27

(27) 44 19% (10) 301 724

(28) 58 26% (10) 643 255

(29) 29 32% (10) 1205 908

(30) 127 39% (10) 790 383

(31) 32 114 11 21

(32) 67 2488 21 68

(33) 135 4243 578 518

(34) 16 1616 304 154

(35) 11 113 15 52

(36) 12 1228 800 289

(37) 11 7803 387 233

(38) 16 901 840 275

(39) 6.8 3203 477 83

(40) 25 1658 166 252

(41) 2.9 1908 160 28

(42) 3.5 1739 228 40

(43) 3.3 47 19 5.4

(44) 4.0 10,000 898 103

(45) 2.9 148 21 12

(46) 7.3 96 51 6.4

(47) 5.0 239 65 26

(48) 7.4 40 11 4.5

(49) 2.4 - - -

(50) 19.9 4244 337 73

(51) 15.2 > 10 µM 914 595

(52) 21.3 5450 510 4.9

TACE: TNF-a converting enzyme.

9 R = H10 R = Me

11 R = H12 R = Me

13 14 R = Me; R′ = H15 R = Ph; R′ = H16 R = Ph; R′ = Me

HO MeC

1917 R = Me18 R = OMe

Heteroaryl acetylenic sulfonamides (78, 79) have exhibitedexcellent TACE inhibitory activity. Compound 78 wasclaimed to have an IC50 value of 11 nM for TACE andvery poor activity against MMP-1, that is, IC50 »10,000 nM [41]. Compound 83 of acetylenic aryl sulfonamidehydroxamic acid derivatives (80 – 83) showed promising resultwith an IC50 value of 6.8 nM for the TACE enzyme [42].

4. TACE inhibitors developed at DarwinDiscovery Ltd

Isotetrahydroquinoline sulfonamide (84) and tricyclic analo-gues, such as compound 85, were prepared in Celltechlaboratories and patented by Darwin Discovery Ltd in2001 for their activity against MMPs and TACE [43,44]. Thesecompounds have been designed from previously publishedsulfone [45] and sulfonamide MMP inhibitors [46] as leads and

offer versatile templates which could be adopted for selectivityagainst different metalloenzymes by modification of aromaticsubstitutents. In the same year, Darwin Discovery also claimedcarboxamides, such as compounds 86 and 87, to providepotent activity against TACE with selectivity overMMPs [47-49].

5. TACE inhibitors developed at Bristol-MyersSquibb Co.

The Bristol-Myers Squibb’s selective TACE inhibitor, BMS-561392 or DPC-333 (88), was derived from IK-682 (89).In vitro IC50 value of the compound (88) is 0.20 nM and inwhole blood assay it is 90 nM. Compound 88 is > 100-foldmore selective against TACE over MMPs. This compound hasshown good (54%) bioavailability in dogs and reasonablebioavailability in rats (16%). In Phase I of clinical studies, it

was observed that the compound was well tolerated amonghealthy human volunteers at a dose range of 15 – 530 mg. Itwas also noted that the half-life of the molecule in humans was3 – 6 h [18].

Substitutedcyclopentylhydroxamates, suchascompound90,are claimed as MMP, aggrecanase and TNF-a inhibitors.Although these compounds are reported to exhibit Ki valuesof £ 10 µM in fluorometric assay for inhibitory activity againstMMP-1 to -3, -7 to -9 and -13 to -16, no specific biological datahave been revealed against TACE [50]. Azetidine carboxamidessuch as compound 91 have been claimed as MMP inhibitorsand TNF antagonists. These compounds bear the substitutedquinoline moiety, present in BMS-561392 (88), andare reported to be selective for TACE over MMPs. However,no specific data have been given [51]. Disubstitutedcyclohexanyllactams, such as compound 92, have been claimed

as potential TACE inhibitors as an outcome of research onIK-682 (89), causing dose-dependent reduction in TNF levelsfollowing D-galactosamine and LPS challenge in mice, whendosed intraperitoneally [52].

A new series of TACE inhibitors was discovered at Bristol-Myers Squibb using a pyrimidine-2,4,6-trione motif as a zinc-binding group in place of hydroxamate. Optimization of theinitial lead (93) resulted in a potent inhibitor (94), with anIC50 value of 2 nM in a porcine TACE (pTACE) assay.Compound 94 has been claimed as the first representativeexample of non-hydroxamate-based TACE inhibitors withsingle digit nanomolar potency [53-55].

A selective and potent inhibitor of TACE that replaces thecommon hydroxamate zinc binding group (ZBG) with hydan-toin has been claimed in two different patents [56,57].Compound 95 containing a phenyl linker between the

29 n = 230 n = 1

31 R = Me32 R = n.Bu

27 R = Cyclobutyl28 R = Me

hydantoin ZBG and the P1¢ moiety shows pTACE inhibitoryactivity with an IC50 value of 14 nM [58].In another patent, a series of novel hydantoins have been

reported by Sheppeck et al. as structural alternatives to hydro-xamate inhibitors of TACE [59,60]. These 5-mono- and di-substituted hydantoins exhibited activity with IC50 values of11 – 60 nM against pTACE, in vitro, and excellent selectivityover other MMPs. Compound 96 showed good selectivity (Ki

values forMMP-1> 4946,MMP-2> 3333,MMP-9> 2128andMMP-13 > 5025) for pTACE (IC50 value of 11 nM). Thestringent requirement for unsubstituted hydantoin nitrogens,the unnatural (5R) stereochemistry and an H-bond acceptorappended to an appropriately functionalized hydrophobic P1¢side chain that complements the MMP S1¢ pocket are whatconfer activity to this new class of molecules [61].In 2006, cyclic sulfone derivatives (97) as inhibitors of

MMP and/or TACE have also been reported [62].Bicyclic lactam derivatives (98 – 100) as TACE inhibitors

have been documented as having beneficial effect in thetreatment of inflammation [63].

Bicyclic hydroxamates (101, 102) have also been claimed asTACE inhibitors in 2004 [64].

A new series having 4-(2-methylquinolin-4-ylmethyl)phenyl P1¢ group along with the b-amino hydroxamic acidhas been reported as a TACE inhibitor, by eliminating theoxygen atom in the linker of the original 4-(2-methylquinolin-4-ylmethoxy)phenyl P1¢ group. Incorporating the new P1¢group onto different b-aminohydroxamic acid cores provideda new series of TACE inhibitors with potent WBA activity.Among them, compound 103 was reported to have goodpharmacokinetic properties and an excellent selectivity profileover the MMPs (pTACE IC50 = 1 nM) [65,66].

Spiro-cyclic b-amino acid derivatives (104, 105) as TACEinhibitors have been patented in 2004 [67]. Both isomers (104and 105) were reported to be extremely potent against pTACE(1.0 nM, each) and also displayed > 1000-fold selectivity forpTACE over MMP -1, -2 and -9. Both the compounds gaveCaco-2values (i.e.,Papp> 1.0�10-6 cm/s) indicativeofgoodoralabsorption with compound (104) demonstrating Papp = 5.7 �10-6 cm/s and compound (105) having Papp = 1.5 � 10-6 cm/s.

35 X = H; Y = Br36 X = Et; Y = Br37 X = CH2OMe; Y = Br38 X = Me; Y = I39 X = CH2OH; Y = Br

Both these compounds (104 and 105) proved to be orally bio-available in Sprague–Dawley rats [68].

Isoxazoline derivatives (106, 107) and uracil derivatives(108, 109) have been claimed by Xue et al. [69] and Maduskuieet al. [70], respectively, as TACE inhibitors; however, nodetailed specific biological data have been presented.

A series of non-hydroxamate inhibitors that use a 1,3,4-triazole-2-thione scaffold as the zinc binding ligand (com-pound 110) have been disclosed by King et al. [71]. The mostpotent compound in the series has an IC50 value of 1.5 nM forpTACE with excellent selectivity over MMP-2, -3, -7, -12 and-13. It has also been proven that the compounds having triazol-ethiones possess intrinsically higher potency than comparablysubstituted barbiturates, hydantoins and triazolones, the otherZBGs, discovered in Bristol Myers Squibb laboratories [72].

6. TACE inhibitors developed at Pfizer Ltd

Pfizer Ltd actively engaged in the field of research onmetalloprotease inhibitors for the treatment of arthritis

and related diseases has staked claim for a number ofpotent TACE inhibitors. A European patent has beenclaimed for compounds (111 – 114) for their TACEinhibitory activity (Table 2). Compound 111 is one ofthe promising compounds as its IC50 value is 4.5 nM forTACE. It shows potent activity (IC50 value 1.4 nM)against MMP-13 but a moderate activity againstMMP-1 (IC50 value 1.4 µM) [73].

Pfizer has patented trisubstituted piperidines that are struc-turally related to prinomastat (115) as selective aggrecanaseinhibitors. These compounds are also claimed to possessTACE inhibitory activity [74]. Such a compound (116) showedIC50 values of < 10 nM for aggrecanase and MMP-13,< 10 nM value for TACE, and between 200 and 1000 nMfor MMP-1. Pfizer also claimed oxoimidazolidine hydroxamicacids, such as compound 117 [75], and pyrimidinetriones, suchas compound 118 [76], to possess TACE inhibitory activity.These two series of compounds claimed to possess TACEinhibitory potentials, but have not been provided withrelevant biological data.

7. TACE inhibitors developed at GlaxoWellcome, Inc.

GlaxoWellcome has been involved in a long-standing researchprogramfor thedevelopmentofMMPandTACE inhibitors. In2001, Andrews et al. have claimed compounds (119 – 127)having reverse hydroxamic acid group as TACE inhibitors inthreedifferentpatents [77-79].TheTACEandMMP-1inhibitoryactivity (Ki) for the compounds 119 – 122 have been claimed [77]

to be in the range of 50 – 500 nM except forMMP-1 inhibitoryactivity for compound 120, which has been claimed to be in therange of 5 – 50 nM value (Table 3). Compound 123 has beenreported to possess < 50 nM Ki value for TACE.

8. TACE inhibitors developed at VertexPharmaceuticals

Research group at Vertex Pharmaceutical were interested inexploring non-hydroxamates as ZBGs, such as thiol, for devel-oping TACE inhibitors. A series of potent thiol-containing arylsulfonamide TACE inhibitors have been patented by Bandarageet al. [80]. One of the compounds (128) has shown excellentin vitro potency against the isolated TACE enzyme(Ki = 28 nM) with 200-fold selectivity over MMP-2 and -7and 40-fold selectivity over MMP-8 and -13 [81].

9. TACE inhibitors developed at KakenPharmaceuticals Co. Ltd

Shimano et al. at Kaken Pharmaceutical Co. Ltd have patentedvery recently compounds having reverse hydroxamic acidgroup. The reported compounds (129 – 135) exhibit a highlyTACE-selective inhibitory action without inhibiting otherMMPs (Table 4) [82]. Compound 129 is the most potentand selective TACE inhibitor in this series having an IC50

value of 1.9 nM.

10. Expert opinion

TNF-a plays a pivotal role in the origin and progression of RAand other immune-mediated disorders. Since the discovery ofanti-TNF-a biologics, much effort has gone into developingan orally bioavailable small molecule TNF-a antagonist.TACE inhibition is an attractive strategy for RA treatmentwhich has been validated in preclinical trials using biologicalsto block TNF-a. But unfortunately, even after more than adecade of research in the field, not even a single small sizeTACE inhibitor has passed the Phase II clinical trials. Manycompounds belonging to different chemical classes have beensynthesized and reported as selective TACE inhibitors. Out ofthese two promising molecules namely, TMI-05 (136) andBMS-561392 (88), have been withdrawn from Phase II clin-ical trials because of lack of efficacy or hepatotoxicity. There isa growing concern among the scientific community whetherTACE inhibitors would really show a favorable

Table 2. In vitro TACE and MMP inhibitory activity.

Comp.no.

IC50 (nM)/% inhibition (µM)

TACE MMP-1 MMP-9 MMP-13

(54) 51.1% 99.1% 79.1% 85.4%

(55) 65% 299 16 12

(56) 42.21% 1000 63 13

(57) 42.33% 1600 131 226

(58) 47.5 413 20.9 31.3

(59) 34.6 304.6 6.3 3.2

(60) 49.9 455.8 233.6 48.2

(61) 36.5 262 50.9 6.2

(62) 27.1 2036 230.9 43.9

(63) 9.7 59.6% 649 148

(64) 22.9 2640 138 28.6

(65) 18.1 4437 374 33.8

(66) 42% 1000 70 296

(67) 294 1227 15 47

(68) 24 456 1 1

(69) 20 301 9 12

(70) 47 22 11 467

(71) 15 > 1 µM 5056 672

(72) 28 > 10 µM >10 µM >10 µM

(73) 30 > 10 µM >10 µM » 10 µM

(74) 14 2768 383 308

(75) 273 6300 2700 679

(76) 362 - - -

(77) 263 - - -

(78) 11 » 10,000 607 478

(79) 44 - - -

(80) 11 113 15 52

(81) 16 1616 304 154

(82) 12 1228 800 289

(83) 6.8 3203 477 83

(111) 4.5 1400 - 1.4

(112) 6.2 1600 - 3

(113) 10 1400 - 88

(114) 7.2 305 - 1.4

pharmacological profile. Could a small TACE inhibitor berecommended for treating RA? Would any small size TACEinhibitor be able to see the day of light as a successful drug fortreating inflammatory disorders such as RA? The fact of thematter is that there are still many promising TACE inhibitorsin the preclinical phase. Hence, it is too early to rule outTACE inhibition as a viable strategy for curing RA. And itshould also be kept in mind that arthritis being a complexmultifactorial disease, inhibition of one particular cytokinealone may not fully succeed in treating RA.Although a few TACE inhibitors have advanced to human

clinic trial stages, so far no TACE inhibitor has reached themarket. This has been attributed partially to the general lack of

selectivity of TACE inhibitors. Thus, development of a highlyselective TACE inhibitor has been a major goal for manyacademic and pharmaceutical industrial research laboratories.The structure of the catalytic sites of TACE and MMPs aresimilar, and both are zinc endopeptidases. Some previouslyidentified MMP inhibitors (marimastat, prinomastat (115)and CGS 27023A (137)) have been found to inhibit TACE aswell. But these compounds failed in clinical trials as theyshowed dose-limiting musculoskeletal side effects [83-85].According to some researchers, the cause for the musculo-skeletal side effects is their ability to inhibit MMP-1 and/orMMP-14, and the therapeutic efficacy of these molecules isdue to their ability to inhibit TACE [86,87]. Hence, it is highly

58 R =

59 R =

60 R =

55 R = Me; R′ =

56 R = R′ =

57 R = i.Bu; R′ =

desirable to develop selective TACE inhibitors devoid of anyMMP inhibitory activity [88,89]. There is a second school ofthought according to which compounds that are active againstTACE as well as MMPs may be more efficacious than aselective TACE inhibitor only, as some of the MMPs are alsooverexpressed in RA. This is the reason why some researchgroups are still engaged in developing a dual TACE andMMP-13 inhibitor which would not touch upon MMP-1 [90-92]. On the other hand, TACE and MMPs are involvedin various normal physiological processes; hence, selective

inhibitors may cause fewer side effects. The optimal MMPselectivity profile for a TACE inhibitor in the treatment of RAis still unknown [93,94]. Another very important issue to beaddressed is the failure of very potent low nanomolarinhibitors of TACE in cells and human whole blood [7].

Identification of selective TACE inhibitors has provedelusive until recently due to structural similarities betweenTACE andMMPs. The differences in the shape and size of theS1¢ pocket of TACE and MMPs might be exploited to designselective TACE inhibitors devoid of any MMP activity [95,96].

Although there exists high three-dimensional structural sim-ilarity among the active sites of TACE and MMPs, the TACEconformational structure around the catalytic zinc ion and thetotal effective charge on this metal ion is very different fromthat of MMPs. It has also been discovered that active site ofTACE is more polar than that of MMPs. Hence, the differ-ences in electronic, structural and kinetic behavior observedamong TACE and MMPs provide a ray of hope for thedesigning of specific TACE inhibitors.

Even after so much advancement in computationalchemistry, very few computational studies have been reported

on the selectivity aspect of TACE inhibitors over MMPs.Hence, there is a great scope to tackle the selectivity problemof TACE inhibitors over the MMPs by considering variouscomputational techniques such as 3D-QSAR, pharmacophoreidentification and structure-based designing for these patentedcompounds. Thus, modeling and QSAR studies of existingTACE inhibitors could help in developing a more potent andselective TACE inhibitor with lesser side effects and betterpharmacokinetic properties. In this review of patented com-pounds, different scaffolds have been disclosed which could beutilized for developing a common pharmacophore for selectiveTACE inhibitors so that the designing of new chemical classesof TACE inhibitors may be rationalized. For developing thepharmacophore model, binding of the inhibitors with theTACE prime site should not be the only consideration, asmolecules binding to the non-prime site of the enzyme havealso been shown to be potent inhibitors of TACE [97].

This review of patented compounds on TACE inhibitorshas thrown open an array of scaffolds having hydroxamate,reverse hydroxamate, barbiturate, hydantoin, thiotriazolone,uracil, thiol, and carboxylate as zinc-binding motifs, andacetylenic, allenic, quinolinic and other carbocyclic/heterocy-clic groupings for interaction at the S1¢ subsite of the enzyme.Some of the compounds have shown good selectivity forTACE over MMPs in the in vitro studies while others havenot show selectivity but exhibited high potency for TACEinhibition. The compounds (129 – 135) reported by Shimanoet al. [82] from Kaken Pharmaceutical although look to possess

Table 3. TACE and MMP activity (Ki values) for the

compounds developed at Glaxo Wellcome.

Comp. no. TACE (nM) MMP-1 (nM) MMP-3 (nM)

(119) 50 – 500 50 – 500 0.001 – 0.5

(120) 50 – 500 5 – 50 0.001 – 0.5

(121) 50 – 500 50 – 500 0.001 – 0.5

(122) 50 – 500 50 – 500 0.001 – -0.5

(123) < 50 500 – 1000 <50

(124) < 50 50 – 250 nM 50 – 250

(125) < 1000 > 1000 100 – 500

(126) 100 – 500 > 1000 500 – 1000

(127) < 100 > 1000 100 – 500

78 R = Me79 R = H

Table 4. Concentration of the reverse hydroxamic acid derivatives required for 50% inhibition of the enzyme activities.

Comp. no. TACE MMP-1 MMP-2 MMP-3 MMP-8 MMP-9 MMP-13 MMP-14 MMP-17

(129) 1.9 1,000,000< 28,000 42,000 23,000 100,000< 32,000 77,000 2200

(130) 2.0 80,000 - 5000 - 45,000 15,000 15,000 3000

(131) 2.0 64,000 30,000 2400 60,000 75,000 32,000 65,000 2200

(132) 2.0 60,000 32,000 1500 73,000 73,000 38,000 74,000 1200

(133) 2.2 35,000 630 50 2650 9000 600 3800 45

(134) 2.9 70,000 18,000 2200 61,000 52,000 20,000 38,000 2300

(135) 2.5 100,000< 34,000 4000 27,000 100,000< 18,000 58,000 2400

similar scaffolds and zinc-binding motif as reported by otherresearchers, but possessed high selectivity for TACE over otherMMPs. In light of the fact that binding subsites of TACE andMMPs are quite similar, it would be a Herculean task todevelop a specific TACE inhibitor for clinical treatmentof RA. But, considering the chemical development of highlyselective TACE inhibitors in the recent years and applicationof molecular modeling studies at a wider scale in the nearfuture, development of more selective clinically useful TACEinhibitors may not remain a distant dream.Recently, the role of TACE has also been implicated in

cancer [98]. It has been shown that TACE is a druggable targetwhich could be used for inhibition of pathogenic EGFRsignaling in cancer. Considering the promiscuous nature ofTACE which could cleave at least 30 membrane-spanning

proteins, inhibition of TACE might be more suitable for adisease such as cancer where potential drugs often have atoxicity profile that is less than ideal [7]. A new TACEinhibitor, namely INCB 3619 (138) is being studied clinicallyas an anticancer agent [99,100]. Some older TACE inhibitors arealso being studied for their anticancer activity. This findinghas not only boosted the concept of development of TACEinhibitors as anti-neoplastic agents but also gives a newdirection to research for development of newer TACEinhibitors.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

(5R,6S)-trans

R′R″

101 102Me

104 X = O; Y = CH2105 X = CH2; Y = O

108 109

111 112

113 114

115 116

117 118

119 120

121 122

Me OMe Me

N H NHN

Me OMe Me

124 125

126 127

– 13

R′ =

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AffiliationPrashant R Murumkar, Shirshendu DasGupta,

Sneha R Chandani, Rajani Giridhar &

Mange Ram Yadav†

†Author for correspondence

Professor, The M.S. University of Baroda,

Faculty of Technology & Engineering,

Department of Pharmacy,

Kalabhavan, Vadodara, 390 001, India

Tel: +91 0265 2434187; Fax: +91 265 2418927;

E-mail: mryadav11@yahoo.co.in

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