Chapter 17 MAP Kinase Inhibitors in Inflammation and Autoimmune Disorders

CHAPT ER

17 MAP Kinase Inhibitors in Inflammation and Autoimmune Disorders Shripad S. Bhagwat

Contents

1. Introduction 2. Inhibitors of ERK Pathway 3. Inhibitors of JNK Pathway 4. Inhibitors of p38 Pathway 5. Conclusion References

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1. INTRODUCTION Cells have evolved to orchestrate gene transcription and other cellular functions by signaling through a variety of intracellular protein mediators such as kinases, phosphatases, ligases and transcription factors. Mitogen-activated protein kinases (MAPKs) are a family of serine, threonine phosphorelay enzymes activated by cytokines, growth factors, stress, immune receptors and G-protein coupled receptors (GPCRs). The phosphorelay system consists of three tiers of kinases, MAPKs, MAPK kinases (MAPKKs or MAP2Ks or MKKs or MEKs) and MAPKK kinases (MAPKKKs or MAP3Ks or MEKKs or MKKKs). The MKKKs transduce cellular signals by phosphorylating and activating MAPKKs, which in turn, phosphorylate and activate MAPKs. Once activated, MAPKs are often translocated to the nucleus and phosphorylate their respective substrates such as transcription factors and/or other effector proteins. The nature of stimuli, cell types and substrates involved in signal transduction dictate the observed pharmacologic effect (Figure 1) [1–4]. Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA Annual Reports in Medicinal Chemistry, Volume 42

r 2007 Elsevier Inc.

ISSN 0065-7743, DOI 10.1016/S0065-7743(07)42017-6

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Stimuli

Activator

MKKK

Growth Factors

Cytokines/Stress/Immune Receptor/GPCR

Ras

Cdc24 / Rac

Raf, Tpl-2

MEKK1-4, TAK1, ASK1/2, MLK

MKK

MEK1, MEK2 (MKK1/2)

MKK3, MKK6

MKK4, MKK7

MAPK

ERK 1/2

p38a/ß/γ/δ

JNK1/2/3

Substrate

ETS, p90 RSK

ATF2, MEF2A/C, C-JUN, MNK, MAPKAPK2

Response Cell Proliferation, Differentiation, Survival, Apoptosis, Tissue Degradation/Destruction

Figure 1

MAP kinase phosphorelay signaling pathways in cells. Stimuli

Scaffolding Proteins regulate MAPK signaling by - organizing signaling complexes -trafficking signaling complexes -facilitating subcellular location of complexes - influencing duration of signal

MKKK Scaffolding Proteins

MKK

MAPK Figure 2

Scaffolding proteins facilitate MAP kinase signaling in cells.

Scaffolding proteins, whose primary role in cells is binding and organizing multiple signaling proteins in a complex and trafficking the complex to appropriate sub-cellular locations, often facilitate the MAPK phosphorelay signal transduction. The type and location of the scaffolding proteins regulates the outcome of the signaling pathway (Figure 2) [5,6]. The three major MAPK families, whose regulation and function have been conserved during evolution in eukaryotic cells, are extracellular

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signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38. In inflammatory cells such as macrophages, stimulation of selected Toll family receptors like TLR4 by microbial pathogens or other immunogenic factors leads to the activation of the ERK pathway [4]. Stimulation of TLR4 activates Tpl-2, a MKKK, which phosphorylates and activates MEK1/2 (MKK1/2) leading to the activation of ERK1/2. Activated ERK1/2 regulates expression of tumor necrosis factor-a (TNFa) and other cytokines, which are the key mediators of inflammation and immune responses. The ERK pathway can also be activated in other cell types, by binding of a growth factor such as epidermal growth factor (EGF) to its receptor resulting in the activation of Ras which then activates Raf serine/threonine kinase (MKKK). Raf kinase phosphorylates MEK1/2 which activates ERK1/2 by phosphorylating its serine/threonine and tyrosine residues leading to mitogenic responses. Activated ERK phosphorylates the transcription factor Elk-1, ribosomal S6 kinase RSK and others. The scaffolding proteins, KSR, MP1 and b-arrestin-1, regulate the signal transduction in the ERK pathway. Signal transduction in the JNK pathway is also largely dependent on scaffolding proteins, sub-cellular location and cell type [4,6]. JNK1, 2 is expressed ubiquitously, while JNK3 is expressed primarily in brain, heart and testes. The scaffolding proteins, JNK inhibitory protein (JIP) and CrkII, facilitate JNK1, 2 mediated signal transduction. The scaffolding proteins bind JNK1, 2, MKK7 or 4 and members of mixed lineage kinase family (MLK) or MEKK1. In neuronal cells, b-arrestin-2 and JIP-1b are the scaffolding proteins that facilitate signaling through ASK1, MKK7 and JNK3. Once activated, JNK is translocated to the nucleus where it phosphorylates transcription factors (AP-1, ATF-2, Elk-1, NFAT and p53) that regulate gene expression of matrix metalloproteases (MMPs) and pro-apoptotic proteins. Activation of JNK1, 2 leads to inflammatory signals, while activation of JNK3 in the brain produces neurodegenerative responses. The stimulus- and location-selective activation of the p38 MAPK pathway is also controlled by the scaffolding proteins, TAB1 and OSM. TAB1 recruits TAK1, MKK4 or 6 and p38, while OSM recruits MEKK3, MKK3 and p38. Activation of p38 leads to phosphorylation and activation of MAPKAPK2 (MK2) and transcription factors such as ATF-2 [3,4]. Activation of p38 pathway primarily leads to inflammatory and autoimmune responses, although mitogenic effects have also been observed. The effect of MAPK activation on cellular processes that affect cell function and the resulting pharmacology has been delineated using modern techniques such as knock-out cells and animals [1,3,6]. Activation of MAPK in inflammatory cells such as T-cells, B-cells, macrophages and eosinophils leads to expression and/or activation of pro-inflammatory genes and mediators such as interleukin1b (IL-1b), TNFa, IL-6, chemokines [e.g., IL-8, macrophage inflammatory factor-1a,b (MIP-1a,b)], MMPs and toxic molecules such as free radicals and nitric oxide [1,3]. These pro-inflammatory mediators induce cellular proliferation, differentiation, survival, apoptosis and tissue degradation/destruction and help induce chronic inflammation. Inhibition of any one or more of the MAPK family

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of enzymes is therefore anticipated to produce beneficial pharmacologic and therapeutic effects [7,8].

2. INHIBITORS OF ERK PATHWAY Inhibitors of Tpl-2 (MKKK), MEK1/2 (MKK1/2) and ERK1/2 have been reported. Macrophages from Tpl-2 knockout mice lack ERK1/2 activation leading to loss of TNFa expression and are insensitive to LPS-induced endotoxin shock [9]. Inhibition of Tpl-2 and MEK1/2 produces potent anti-inflammatory effects in cellular and animal models. A series of naphthyridine- and quinoline-3-carbonitriles, compounds 1, 2 have been reported to be potent Tpl-2 inhibitors with IC50 values ¼ 2 and 19 nM, respectively [10,11]. Compound 1 was selective against a series of six kinases known to regulate TNFa production including the downstream Tpl-2 substrate MEK1 (IC50 ¼ 630 nM). However, due to its poor activity in whole blood (IC50 ¼ 13.6 mM) [10], its solubility, cell permeability and protein binding needed significant improvement. Compound 2 on the other hand, inhibited Tpl-2 with an IC50 ¼ 19 nM and showed improved selectivity and improved physical properties leading to increased whole blood potency (IC50 ¼ 3.3 mM). When administered intraperitoneally to mice at 25 mg/kg dose, 2 inhibited LPS-induced TNFa production by 70% [11]. A number of MEK1/2 inhibitors have been reported to display anti-inflammatory properties. PD98059, an ATP non-competitive, flavone derivative, inhibits the inactive form of MEK1/2 with IC50 ¼ 2–10 mM by blocking the phosphorylation required for its activation [12,13]. PD98059 is a fairly specific inhibitor of MEK1/2 because it does not inhibit phosphorylation mediated by c-Raf, JNK, p38, PKA, PKC, n-Src, the active form of MEK1/2 and several other serine/ threonine and protein tyrosine kinases. Efficacy with PD98059 has been demonstrated in animal models of pain, arthritis and asthma [14–16]. F

N O

HN

HN

H N

CN N

H N

N

HN

N

N 1

O

2

NH2 CN

OCH3 NH2

O PD98059

Cl CN

S NH2

NH2 S

CN NH2 U0126

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O

H N

O

O

Cl

H N F

H N

O H N

I

H N

O

F

H N

PD-198306

HO

F

O

N

F O

ARRY-438162

Br

F

I

F

H N

PD-325901

F

O H N

Cl

H N N

H3C

H N

F

CI-1040 (PD-184352)

O

O OH

F

F

I

HO

CH3

H N

F

HO

O

H3C N

F N

ARRY-142886

Br

NH

O

Cl

HN Cl

OH

3

U0126 represents another ATP non-competitive and selective inhibitor of MEK1/2 with no activity toward Raf, MEKK, ERK, MKK-3, -4 and -6 [17]. Activity of U0126 in cells is also limited to those with ERK pathway activation. For example, U0126 inhibited ras-transformed cell growth without affecting normal cells. In an adjuvant-induced arthritis model in rats, U0126 inhibited hyperalgesia to heat and mechanical sources [18]. CI-1040 (PD-184352) is a potent and selective ATP non-competitive inhibitor of MEK1 and MEK2 with IC50 ¼ 17 nM for purified MEK1 [19]. The compound inhibits phospho-ERK (pERK) and proliferation of a number of relevant cells with IC50 ¼ 100–200 nM and inhibits tumor growth in xenograft models. As a result, this compound did progress through Phase I clinical trials for the treatment of cancer however was later dropped from further investigation due to less than expected efficacy in Phase II [20]. The exquisite MEK1/2 selectivity of this compound is explained by the observation that in the X-ray structure of analogs of CI-1040 in MEK1 and MEK2, the inhibitors bind in a hydrophobic pocket adjacent to but distinct from the ATP-binding site which may not be available in other kinases [21]. It is likely that the structurally similar and ATP non-competitive MEK1/2 inhibitors discussed below have a similar binding mode in the active site. The second generation compound PD-198306 is a structurally close analog of CI-1040 that inhibits MEK1/2 with IC50 ¼ 8 nM and MEK activity in synovial fibroblasts at concentrations of 30–100 nM, depending on the species [22]. The paper mentions (without any data) that this selective MEK inhibitor has good oral bioavailability (F ¼ 62%) and is efficacious in a number of arthritis models in rats including streptococcal cell wall and adjuvant-induced arthritis (ED50 values ¼ 11.2 and 6.6 mg/kg, respectively). The authors demonstrate efficacy of PD-198306 in a rabbit model of osteoarthritis when administered at 30 mg/kg orally. At this dose, there was nearly 50% reduction in the area of cartilage macroscopic lesions, in synovial inflammation and in pERK levels in the cartilage.

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PD-325901 is another analog of CI-1040 that is also a potent, selective and ATP non-competitive inhibitor of MEK1/2 [23]. The compound inhibited MEK1 with Ki ¼ 1.1 nM, MEK2 with Ki ¼ 0.79 nM and pERK in C26 cells with IC50 ¼ 0.43 nM. PD-325901 is efficacious in a number of xenograft models and is currently in Phase I/II trials in cancer patients. ARRY-438162 is a recently disclosed potent and selective ATP non-competitive MEK1/2 inhibitor that is in Phase Ib clinical trials as an anti-arthritic agent [24]. ARRY-438162 inhibited the MEK1/2 enzyme with an IC50 ¼ 12 nM and pERK in cells with an IC50 ¼ 11 nM. ATP non-competitive inhibition may be responsible for equipotent inhibition of MEK1/2 in vitro and pERK in cells. The compound was selective against a panel of 220 other kinases. ARRY-438162 was found to be efficacious in a number of animal models of inflammation. For example, in a collagen-induced arthritis model in rats, oral administration of ARRY-438162 at 10 mg/kg q.d. significantly inhibited paw swelling which was accompanied by inhibition of cartilage damage in the joint and 480% inhibition of pERK in the tissue from the foot with induced arthritis. In a Phase Ia study in healthy volunteers, ARRY-438162 was well tolerated up to 20 mg/kg q.d. oral dose. There was a dose proportional increase in plasma concentration and decrease in the production of IL-1b, TNFa, IL-6 and pERK in the ex-vivo-stimulated whole blood from drug treated volunteers. Array has initiated a Phase Ib study of ARRY-438162 in combination with methotrexate in rheumatoid arthritis patients with the goals of assessing safety, tolerability, pharmacokinetics (PK), biomarkers and initial signs of efficacy. ARRY-142886 (AZD6244) is another potent, selective and ATP non-competitive MEK1/2 inhibitor with IC50 ¼ 12 nM. This compound inhibited cellular pERK with an IC50o 10 nM and tumor growth in a number of xenograft models and is reported to be in Phase II clinical trials in cancer patients [25]. To date the only ERK1/2 inhibitor reported is compound 3 with IC50 ¼ 2 nM for the inhibition of ERK2 [26]. This compound inhibited proliferation of the Colo205 cell line with IC50 ¼ 540 nM and was selective against 12 other kinases. During the optimization of in vitro activity of this series of compounds, it was discovered that the binding modes of an analog of 3 to ERK2 and JNK3 are significantly different.

3. INHIBITORS OF JNK PATHWAY Inhibitors of MLK (MKKK) [27], MKK4, 7 and JNK [6,28,29] have been disclosed to date. CEP-1347, a semi-synthetic analog of the natural product K252a, inhibits MLKs in the JNK pathway with Ki ¼ 17 nM [30–32]. This compound has shown neuroprotective effects in cellular and animal models [33]. CEP-1347, an orally available compound that was well tolerated in the clinic, was advanced to Phase II/III trials for assessing efficacy in Parkinson’s disease. However, the clinical trial was stopped due to a lack of significant efficacy [34].

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Compounds 4 and 5 and their analogs have been disclosed as MKK4 and 7 inhibitors [35,36]. The compounds in these patent applications are claimed to inhibit the two enzymes with IC50 o1 mM; no information on kinase specificity or other biological properties was disclosed. There are numerous other compounds that are disclosed in the patent literature to inhibit many kinases including MKK4 and 7; such compounds are not listed here. H N

O R

R N

O

H

HO

N CH3 OMe

CH3

CONH2

HO

OH

N NH

NH N

N N

O K252a, R=H CEP-1347, R=CH2SCH2CH3

N H

H3C

N H

N

4

O SP-600125

5

A number of distinct chemotypes have been reported as JNK inhibitors. In addition, a significant number of p38 inhibitors have also been found to have JNK inhibitory activity. This review will primarily focus on specific JNK inhibitors which have little or no p38 activity. SP-600125 was one of the first JNK inhibitors to be reported with potent JNK 1, 2 and 3 inhibitory activity (IC50 ¼ 40, 40 and 90 nM, respectively) [37]. This tool compound has been studied extensively in a variety of cellular and animal models of inflammation and neuroprotection, among others. The profile of SP-600125 has been discussed in a number of reviews [6,28,29] and will not be discussed here. CC-401, whose structure has not yet been reported, is a potent and selective inhibitor of JNK1, 2 and 3 (pan-JNK inhibitor), that has been advanced to Phase II clinical trials [38]. Celgene has disclosed analogs of compounds 6 and 7 as JNK inhibitors [39,40]. However, a recent patent application claims the crystal forms and other properties of 8, suggesting that it is likely to be a clinical candidate [41]. F O CONH2

N N S

N H 6

HN N

N N

N

N

N H

N N H 7

N N H 8

Two series of aminopyridine carboxamide derivatives have been reported to be potent, selective and ATP-competitive pan-JNK inhibitors [42–45]. Compound 9 containing a 6-aminophenylacetamide group inhibits JNK1 and JNK2 with IC50

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values of 36 and 70 nM, respectively and inhibits p-c-jun in HepG2 cells with an IC50 ¼ 1.7 mM. The compound inhibited JNK3 with similar potency [42]. The X-ray structure of an analog of 9 complexed to the JNK1 enzyme indicated that while hydrophobic interactions contribute to significant binding interactions, the NH- of the 4-amino group and the oxygen of the 6-aminocarboxamide group form weak H-bonding interactions with the backbone residues of Glu109 and Met111, respectively. The authors hypothesize that these weak backbone interactions could be the reason for the 4100-fold selectivity of this series of compounds against a panel of 74 kinases. Compound 9 showed a desirable PK profile in Sprague–Dawley (SD) rats at a dose of 5 mg/kg p.o. with AUC of 1.5 mg h/mL and good oral bioavailability (F ¼ 49%). An analog of 9 containing a cyano group in place of the chloro- showed a similar overall profile. The efficacy profile of 9 and analogs has not been reported to date. O OCH3

O S

NH2 O N H

OCH3 9

N

O

O Cl O

OH

NH2

S

Cl H N

N O

10

O

N N H

N

N H

CONH2

11

A ‘‘reverse amide’’ analog, 10, also has been reported to be a potent, selective and ATP-competitive pan JNK inhibitor [43]. Compound 10 inhibited JNK1 and 2 with IC50 values ¼ 24 and 74 nM, respectively and inhibited p-c-jun in HepG2 cells with IC50 ¼ 480 nM. At a 5 mg/kg oral dose in SD rats, the PK profile of 10 appeared to be superior to 9 with an AUC ¼ 15.4 mg h/mL and %F4100. Compound 11 has been reported to be a potent JNK1 inhibitor (IC50 ¼ 9 nM) with selectivity against a panel of 12 kinases [46]. The IC50 for inhibition of phosphorylation of c-jun in HEPG2 cells was found to be 1.2 mM. AS600292, AS601245 and their analogs have been reported to be pan JNK inhibitors [47,48]. AS600292 inhibits JNK2 and 3 with IC50 values ¼ 520 and 150 nM, respectively, and has significant selectivity against a panel of 80 other kinases [47]. In a cell assay assessing JNK3 activity, AS600292 inhibited anti-NGF antibody-induced neuronal apoptosis of SCG cells with an IC50 ¼ 1.7 mM. The shape of neurons appeared to be normal indicating no compound-related cytotoxicity. AS600292 and analogs were found to have poor water solubility (1 mg/mL in PBS) and a poor PK profile (i.v., i.p. and p.o.) in rats. AS601245 has been reported to be an ATP-competitive inhibitor of JNK1, 2 and 3 with IC50 values ¼ 150, 220 and 70 nM, respectively, with minimal to no activity in a panel of 25 other kinases [48]. In Jurkat T-cells, AS601245 at 10 mM inhibited IL-2 production induced by phorbol-12-myristate-13-acetate (PMA) by 90%. The weaker cell activity could be due to poor cell permeability. The oral bioavailability of AS601245 in rats was 38%. In mice, AS601245, when dosed at 60 mg/kg p.o. in a developed arthritis model induced by collagen, showed

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moderate beneficial effects as measured by paw swelling and histopathological analysis of the joint. N N N

Cl

H N O

S

S O

N

NH N H N

N O

S

AS600292

N

CN

AS601245 O

N

CN N

S

N O N AS602801

AS602801 has been reported to inhibit JNK1 and 2 with IC50 ¼ 80 and 90 nM, respectively, and JNK3 with IC50 ¼ 230 nM [49]. The compound was selective against a panel of 100 other kinases. Anti-inflammatory effects of AS602801 have been demonstrated by measuring inhibition of TNFa release upon LPSstimulation and by demonstrating protective effects in animal models of multiplesclerosis (MS), lung inflammation and fibrosis. AS602801 showed good bioavailability in rats (F ¼ 50%) with 98% brain penetration. In a Phase I study in normal volunteers, 80–570 mg b.i.d. oral doses of AS602801 were well tolerated and the drug showed a desirable PK profile in humans. The efficacy of AS602801 is being evaluated in patients with MS. The indazole derivatives 12, 13 have been reported to inhibit JNK1 and JNK3, respectively [50,51]. Compound 12 is reported to inhibit JNK1 with a pIC50 ¼ 6.8 and to have good oral bioavailability in rats (F ¼ 50%) [50]. Compound 13 inhibits JNK3, JNK1 and p38a with IC50 values of 3, 101 and 903 nM, respectively [51]. The binding modes of compounds 12 and 13 complexed to JNK1 and JNK3, respectively, have been determined using X-ray crystallography, however, additional biological data have not been disclosed. Compound 14 has also been reported to inhibit JNK3, JNK1 and p38a with IC50 values of 7, 384 and 180 nM, respectively. This compound was found to have oral bioavailability of 16% in rats. Additional biological data have not been reported [52]. The enantiomers of 15, with structural similarity to the imidazole-based p38 inhibitors, have been reported to be potent inhibitors of JNK3 (IC50
3 nM) and p38 (IC50
30 nM) with significant neuroprotective effects in cells [53]. Recent patent literature disclosures include a number of JNK inhibitors with little or no biological data reported. This review will focus on some of the patent applications that have appeared after the publication of reviews that covered the patent literature through 2004 [6,28,29]. Compound 16 and analogs are claimed as sub-micromolar inhibitors of JNK1 [54]. The pyrrolo-triazine 17 and analogs are claimed as equipotent, sub-micromolar inhibitors of JNK2 and p38a [55]. Aminopurines similar to 18 have been claimed as pan-JNK inhibitors with IC50 values ¼ 0.001–10 mM [56]. Imidazo-pyrazine derivatives like 19, are claimed in

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a patent application as pan-JNK inhibitors. Compound 19 inhibits the JNK isoforms with IC50 values o200 nM [57]. Me2N

H N CO2H

O

O

HN

N

N N H

N

NHCOCH3 Cl

N H

N H

12

13 F O

NH

HN

N

O

N

HN N

N

N O

O

N H

S OH

HN 14

NH

H N

N

N

N

Cl

15

16

H N

OH H N NH

Me N N

O

N

N

NH

N HN

HN

F

N

Me O

N

S

N

N

N

O

N

N H

O 17

18

19

4. INHIBITORS OF p38 PATHWAY A large number of p38 inhibitors have been discovered in the past 15 years. Many excellent reviews cover this topic well [58–60] and hence will not be discussed here. Compounds that specifically inhibit MKK3 and/or 6 or upstream kinases at the MKKK level in the p38 pathway have not been reported to date, although a number of patents on kinase inhibitors disclose compounds that inhibit MKK3, 6 along with a list of other kinases. PH-089 is a potent, selective and ATPcompetitive MK2 (MAPKAPK2) inhibitor with IC50 ¼ 126 nM [61]. The compound inhibited TNFa production in human peripheral blood monocytes (PBMC) with IC50 ¼ 1.08 mM. PH-089 at an oral dose of 60 mg/kg, b.i.d., inhibited paw swelling by 55% in a streptococcal cell wall-induced arthritis model in rats. This result is in line with the data from the MK2 knock-out mice which were resistant to collagen-induced arthritis [62]. Compound 20 has also been claimed in a patent application as a MK2 inhibitor with no activity information [63]. Compound 21 has been reported to be a potent inhibitor of MK2 (IC50 ¼ 130 nM) with the ability to inhibit PMA-induced TNFa production in U937 cells (IC50 ¼ 130 nM) [64].

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At a dose of 20 mg/kg i.p., 21 inhibited LPS-induced TNF production in Lewis rats by 68%. Compound 22 and analogs are reported to inhibit MK2 with IC50 o2 mM [65]. NMe2

N F

NH

HN

Cl

HN

O N N PH-089

20 OEt NH2

HO HO

CN O

N

NH2

HN Me

N N N

21

NH

O 22

5. CONCLUSION The search for potent and selective p38 inhibitors has been ongoing for more than 15 years. More than a dozen p38 inhibitors have been advanced to clinical trials however none has been approved for human use yet. It is hoped that the newest generation of p38 inhibitors will be suitable for treating inflammation and autoimmune disorders. Discovery of drugs inhibiting other targets in the MAP kinase pathway has received increased attention in the past decade. A number of MEK and JNK inhibitors are currently being evaluated for safety and efficacy in a variety of indications including inflammation and cancer. It remains to be seen if these drugs will make it to the market. It is anticipated that novel drugs inhibiting additional targets in the MAP kinase pathways will be discovered, advanced to clinical trials and found useful for treating human diseases in the coming years.

REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9]

C. Dong, R. J. Davis and R. A. Flavell, Annu. Rev. Immunol., 2002, 20, 55. W. Duan and W. S. F. Wong, Curr. Drug Targets, 2006, 7, 691. B. Kaminska, Biochim. Biophys. Acta, 2005, 1754, 253. G. L. Johnson, H. G. Dohlman and L. M. Graves, Curr. Opin. Chem. Biol., 2005, 9, 325. T. Pawson, Cell, 2004, 116, 191. A. M. Manning and R. J. Davis, Nature Rev. Drug Disc., 2003, 2, 554. C. J. Malemud, Mini Rev. Med. Chem., 2006, 6, 689. I. M. Adcock, K. F. Chung, G. Caramori and K. Ito, Eur. J. Pharmacol., 2006, 533, 118. C. D. Dumitru, J. D. Ceci, C. Tsatsanis, D. Kontoyiannis, K. Stamatakis, J.-H. Lin, C. Patriotis, N. A. Jenkins, N. G. Copeland, G. Kollias and P. N. Tsichlis, Cell, 2000, 103, 1071.

276

S.S. Bhagwat

[10] L. K. Gavrin, N. Green, Y. Hu, K. Janz, N. Kaila, H.-Q. Li, S. Y. Tam, J. R. Thomason, A. Gopalsamy, G. Ciszewski, J. W. Cuozzo, J. P. Hall, S. Hsu, J.-B. Telliez and L.-L. Lin, Bioorg. Med. Chem. Lett., 2005, 15, 5288. [11] Y. Hu, N. Green, L. K. Gavrin, K. Janz, N. Kaila, H.-Q. Li, J. R. Thomason, J. W. Cuozzo, J. P. Hall, S. Hsu, C. Nickerson-Nutter, J.-B. Telliez, L.-L. Lin and S. Tam, Bioorg. Med. Chem. Lett., 2006, 16, 6067. [12] D. T. Dudley, L. Pang, S. J. Decker, A. J. Bridges and A. R. Saltiel, Proc. Natl. Acad. Sci. USA, 1995, 92, 7686. [13] D. R. Alessi, A. Cuenda, P. Cohen, D. T. Dudley and A. R. Saltiel, J. Biol. Chem., 1995, 270, 27489. [14] Z.-Y. Zhuang, P. Gerner, C. J. Woolf and R.-R. Ji, Pain, 2005, 114, 149. [15] C. D. Cruz, F. L. Neto, J. Castro-Lopes, S. B. McMahon and F. Cruz, Pain, 2005, 116, 411. [16] F. Tsang, A. H. M. Koh, W. L. Ting, P. T. H. Wong and W. S. F. Wong, Br. J. Pharmacol., 1998, 125, 61. [17] M. F. Favata, K. Y. Horiuchi, E. J. Manos, A. J. Daulerio, D. A. Stradley, W. S. Feeser, D. E. Van Dyk, W. J. Pitts, R. A. Earl, F. Hobbs, R. A. Copeland, R. L. Magolda, P. A. Scherle and J. M. Trzaskos, J. Biol. Chem., 1998, 273, 18623. [18] R.-R. Ji, K. Befort, G. J. Brenner and C. J. Woolf, J. Neurosci., 2002, 22, 478. [19] J. S. Sebolt-Leopold, D. T. Dudley, R. Herrera, K. V. Becelaere, A. Wiland, R. C. Gowan, H. Tecle, S. D. Barrett, A. Bridges, S. Przybranowski, W. R. Leopold and A. R. Saltiel, Nat. Med., 1999, 5, 810. [20] P. M. LoRusso, A. A. Adjei, M. Varterasian, S. Gadgeel, J. Reid, D. Y. Mitchell, L. Hanson, P. DeLuca, L. Bruzek, J. Piens, P. Asbury, K. V. Becelaere, R. Herrera, J. Sebolt-Leopold and M. B. Meyer, J. Clin. Oncol., 2005, 23, 5281. [21] J. F. Ohren, H. Chen, A. Pavlovsky, C. Whitehead, E. Zhang, P. Kuffa, C. Yan, P. McConnell, C. Spessard, C. Banotai, W. T. Mueller, A. Delaney, C. Omer, J. Sebolt-Leopold, D. T. Dudley, I. K. Leung, C. Flamme, J. Warmus, M. Kaufman, S. Barrett, H. Tecle and C. A. Hasemann, Nat. Struct. Mol. Biol., 2004, 11, 1192. [22] J.-P. Pelletier, J. C. Fernandes, J. Brunet, F. Moldovan, D. Schrier, C. Flory and J. Martel-Pelletier, Arthritis Rheum., 2003, 48, 1582. [23] P. LoRusso, S. Krishnamurthi, J. R. Rinehart, L. Nabell, G. Croghan, M. Varterasian, S. S. Sadis, S. S. Menon, J. Leopold and M. B. Meyer, Paper presented at the 41st Annual meeting of the American Society of Clinical Oncology, May 13–17, 2005, Orlando, Florida, Abstract 3011 (J. Clin. Onc., 2005, 23, 16S, Part I, 3011). [24] K. Koch, Fourteenth International Conference of the Inflammation Research Association, October 15–19, 2006, Cambridge, MD, USA, Abstract SA40. [Arthritis Rheum. 2006, 54 (Suppl.), Abstr. 794] The slides are available on Array Biopharma Inc. company website: www. arraybiopharma.com [25] J. Lyssikotos, 97th Annual Meeting of the American Association for Cancer Research, April 1–5, 2005, Anaheim, CA, USA. The slides are available on Array Biopharma Inc. company website: www.arraybiopharma.com [26] A. M. Aronov, C. Baker, G. W. Bemis, J. Cao, G. Chen, P. J. Ford, U. A. Germann, J. Green, M. R. Hale, M. Jacobs, J. W. Janetka, F. Maltais, G. Martinez-Botella, M. N. Namchuk, J. Straub, Q. Tang and X. Xie, J. Med. Chem., 2007, 50, 1280. [27] K. A. Gallo and G. L. Johnson, Nat. Rev. Mol. Cell Biol., 2002, 3, 663. [28] G. Liu and C. M. Rondinone, Curr. Opin. Invest. Drugs, 2005, 6, 979. [29] L. Resnick and M. Fennell, Drug Disc. Today, 2004, 9, 932. [30] A. C. Maroney, J. P. Finn, T. J. Connors, J. T. Durkin, T. Angeles, G. Gessner, Z. Xu, S. L. Meyer, M. J. Savage, L. A. Greene, R. W. Scott and J. L. Vaught, J. Biol. Chem., 2001, 276, 25302. [31] M. Kaneko, Y. Saito, H. Saito, T. Matsumoto, Y. Matsuda, J. L. Vaught, C. A. Dionne, T. S. Angeles, M. A. Glicksman, N. T. Neff, D. P. Rotella, J. C. Kauer, J. P. Mallamo, R. L. Hudkins and C. Murakata, J. Med. Chem., 1997, 40, 1863. [32] M. S. Saporito, E. M. Brown, M. S. Miller and S. Carswell, J. Pharmacol. Exp. Ther., 1999, 288, 421. [33] A. C. Maroney, J. P. Finn, D. Bozyczko-Coyne, T. M. O’Kane, N. T. Neff, A. M. Tolkovsky, D. S. Park, C. Y. I. Yan, C. M. Troy and L. A. Greene, J. Neurochem., 1999, 73, 1901. [34] P. Waldmeier, D. Bozyczko-Coyne, M. Williams and J. L. Vaught, Biochem. Pharmacol., 2006, 72, 1197.

MAP Kinase Inhibitors in Inflammation and Autoimmune Disorders

277

[35] H. Sato, T. Inoue, T.-W. Ly, A. Muramatsu, M. Shimazaki, K. Urbahns, F. Gantner, H. Okigami, K. B. Bacon, H. Komura, N. Yoshida and N. Tsuno, WO Patent 04058764, 2004. [36] T. Lowinger, M. Shimazaki, H. Sato, K. Tanaka, N. Tsuno, K. Marx, M. Yamamoto, K. Urbahns, F. Gantner, H. Okigami, K. Nakashima, K. Takeshita, K. Bacon, H. Komura and N. Yoshida, WO Patent 03037898, 2003. [37] B. L. Bennett, D. T. Sasaki, B. W. Murray, E. C. O’Leary, S. T. Sakata, W. Xu, J. C. Leisten, A. Motiwala, S. Pierce, Y. Satoh, S. S. Bhagwat, A. M. Manning and D. W. Anderson, Proc. Natl. Acad. Sci. USA, 2001, 98, 13681. [38] B. L. Bennett, JNK – A Central Effector of Cell Stress Response, 6th World Congress on Inflammation, August 2–6, 2003, Vancouver, Canada. [39] A. Kois, K. J. MacFarlane, Y. Satoh, S. S. Bhagwat, J. S. Parnes, M. S. S. Palanki and P. E. Erdman, WO Patent 0246170, 2002. [40] S. S. Bhagwat, Y. Satoh, S. T. Sakata, C. A. Buhr, R. Albers, J. Sapienza, V. Plantevin, Q. Chao, K. Sahasrabudhe and R. Ferri, US Patent 6897231, 2005. [41] M. Saindane and C. Ge, WO Patent 06130297, 2006. [42] B. G. Szczepankiewicz, C. Kosogof, L. T. J. Nelson, G. Liu, B. Lui, H. Zhao, M. D. Serby, Z. Xin, M. Liu, R. J. Gum, D. L. Haasch, S. Wang, J. E. Clampit, E. F. Johnson, T. H. Lubben, M. A. Stashko, E. T. Olejniczak, C. Sun, S. A. Dorwin, K. Haskins, C. Abad-Zapatero, E. H. Fry, C. W. Hutchins, H. L. Sham, C. M. Rondinone and J. M. Trevillyan, J. Med. Chem., 2006, 49, 3563. [43] H. Zhao, M. D. Serby, Z. Xin, B. G. Szczepankiewicz, M. Liu, C. Kosogof, B. Liu, L. T. J. Nelson, E. F. Johnson, S. Wang, T. Pederson, R. J. Gum, J. E. Clampit, D. L. Haasch, C. Abad-Zapatero, E. H. Fry, C. Rondinone, J. M. Trevillyan, H. L. Sham and G. Liu, J. Med. Chem., 2006, 49, 4455. [44] G. Liu, H. Zhao, B. Liu, M. Liu, C. Kosogof, B. G. Szczepankiewicz, S. Wang, J. E. Clampit, R. J. Gum, D. L. Haasch, J. M. Trevillyan and H. L. Sham, Bioorg. Med. Chem. Lett., 2006, 16, 5723. [45] G. Liu, H. Zhao, B. Liu, Z. Xin, M. Liu, M. D. Serby, N. L. Lubbers, D. L. Widomski, J. S. Polakowski, D. W. A. Beno, J. M. Trevillyan and H. L. Sham, Bioorg. Med. Chem. Lett., 2007, 17, 495. [46] M. Liu, S. Wang, J. E. Clampit, R. J. Gum, D. L. Haasch, C. M. Rondinou, J. M. Travillyan, C. Abad-Zapatero, E. H. Fry, H. L. Sham and G. Liu, Bioorg. Med. Chem. Lett., 2007, 17, 668. [47] T. Ruckle, M. Biamonte, T. Grippi-Vallotton, S. Arkinstall, Y. Cambet, M. Camps, C. Chabert, D. J. Church, S. Halazy, X. Jiang, I. Martinou, A. Nichols, W. Sauer and J.-P. Gotteland, J. Med. Chem., 2004, 47, 6921. [48] P. Gaillard, I. Jeanclaude-Etter, V. Ardissone, S. Arkinstall, Y. Cambet, M. Camps, C. Chabert, D. Church, R. Cirillo, D. Gretener, S. Halazy, A. Nichols, C. Szyndralewiez, P.-A. Vitte and J.-P. Gotteland, J. Med. Chem., 2005, 48, 4596. [49] J.-P. Gotteland, Fourteenth International Conference of the Inflammation Research Association, October 15–19, 2006, Cambridge, MD, USA, Abstract SA41. [Arthritis Rheum., 2006, 54 (Suppl.), Abstr. 795.] [50] M. J. Stocks, S. Barber, R. Ford, F. Leroux, S. St-Gallay, S. Teague and Y. Xue, Bioorg. Med. Chem. Lett., 2005, 15, 3459. [51] B.-M. Swahn, F. Huerta, E. Kallin, J. Malmstrom, T. Weigelt, J. Viklund, P. Womack, Y. Xue and L. Ohberg, Bioorg. Med. Chem. Lett., 2005, 15, 5095. [52] B.-M. Swahn, Y. Xue, E. Arzel, E. Kallin, A. Magnus, N. Plobeck and J. Viklund, Bioorg. Med. Chem. Lett., 2006, 16, 1397. [53] P. Graczyk, A. Khan, G. S. Bhatia, V. Palmer, D. Medland, H. Numata, H. Oinuma, J. Catchick, A. Dunne, M. Ellis, C. Smales, J. Whitfield, S. J. Neame, B. Shah, D. Wilton, L. Morgan, T. Patel, R. Chung, H. Desmond, J. M. Staddon, N. Sato and A. Inoue, Bioorg. Med. Chem. Lett., 2005, 15, 4666. [54] S. King, S. Teague, Y. Xue and B.-M. Swahn, WO Patent 03051277, 2003. [55] Q. Dong, WO Patent 06047354, 2006. [56] R. Albers, L. Ayala, S. S. Clareen, M. Delgado, R. Hilgraf, S. Hegde, K. Hughes, A. Kois, V. Plantevin-Krenitsky, M. McCarrick, L. Nadolny, M. Palanki, K. Sahasrabudhe, J. Sapienza, Y. Satoh, M. Sloss, E. Sudbeck and J. Wright, WO Patent 06076595, 2006. [57] V. Birault, C. J. Harris and S. A. Harrison, WO Patent 05085252, 2005.

278

[58] [59] [60] [61]

[62] [63] [64] [65]

S.S. Bhagwat

J. Westra and P. C. Limburg, Mini Rev. Med. Chem., 2006, 6, 867. J. Hynes and K. Leftheris, Curr. Topics Med. Chem., 2005, 5, 967. C. Dominguez, D. A. Powers and N. Tamayo, Curr. Opin. Drug Disc., 2005, 8, 421. R. Mourey, G. Anderson, J. Hirsch, M. Meyers, S. Mnich, L. Stillwell, M. Thiede, W. Vernier, E. Webb, J. Zhang, M. Gaestel and J. Monahan, poster abstract A142, 14th International Conference of the Inflammation Research Association, October 15–19, 2006, Cambridge, MD, USA. A. Kotlyarov, A. Neininger, C. Schubert, R. Eckert, C. Birchmeier and H. Volk, Nat. Cell Biol., 1999, 1, 94. J. K. Dickson, K. P. Williams and C. N. Hodge, US Patent 0009460, 2006. D. R. Anderson, S. Hegde, E. Reinhard, L. Gomez, W. F. Vernier, S. Liu, A. Sambandam, P. Snider and L. Masih, Bioorg. Med. Chem. Lett., 2005, 15, 1587. T. Kosugi, M. Imai, H. Makino, M. Takakuwa, G. Unoki, K. Kataoka, D. R. Mitchell, D. J. Simpson, C. J. Harris, J. Le and Y. Yamakoshi, US Patent 0135514, 2006.