Bioorganic & Medicinal Chemistry Letters 22 (2012) 1433–1438

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier .com/ locate/bmcl

Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor

Véronique Plantevin Krenitsky ⇑, Lisa Nadolny, Mercedes Delgado, Leticia Ayala, Steven S. Clareen,Robert Hilgraf, Ronald Albers, Sayee Hegde, Neil D’Sidocky, John Sapienza, Jonathan Wright,Meg McCarrick, Sogole Bahmanyar, Philip Chamberlain, Silvia L. Delker, Jeff Muir, David Giegel, Li Xu,Maria Celeridad, Jeff Lachowitzer, Brydon Bennett, Mehran Moghaddam, Oleg Khatsenko, Jason Katz,Rachel Fan, April Bai, Yang Tang, Michael A. Shirley, Brent Benish, Tracey Bodine, Kate Blease,Heather Raymon, Brian E. Cathers, Yoshitaka SatohCelgene Corporation, 4550 Towne Centre Court, San Diego, CA 92121, USA

a r t i c l e i n f o

Article history:Available online 10 December 2011

Keywords:Idiopathic pulmonary fibrosisJun N-terminal kinaseAminopurine-based JNK inhibitorsCC-930Structure-based drug design

0960-894X/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.bmcl.2011.12.027

⇑ Corresponding author. Tel.: +1 858 795 4774; faxE-mail address: vplantev@celgene.com (V. Plantev

a b s t r a c t

In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors.Improving the physico-chemical properties as well as increasing the potency and selectivity of a subser-ies with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentia-tion based on PK profiles in multiple species as well as activity in a chronic efficacy model led to theidentification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.

� 2011 Elsevier Ltd. All rights reserved.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease manifestedby a progressive loss of lung function through fibrotic changes inthe lung tissue.1 Since effectiveness of currently available drugtreatment is modest at best,2 novel approaches to treat the diseaseare highly desirable. As described in our previous publication, po-tent and selective aminopurine-based Jun N-terminal kinase (JNK)inhibitors demonstrated pharmacological efficacy in animal mod-els of acute inflammation and tissue damage.3 In addition,SP600125, an early JNK inhibitor with modest selectivity for JNKover p38 and ERK MAP kinases,4 showed efficacy in a number ofanimal models of fibrosis.5 In this Letter, we present the identifica-tion of 1 (CC-930), and the pharmacological profile of this com-pound in animal models of inflammation and fibrosis.

Early optimization of a trisubstituted diaminopurine scaffold asa new class of JNK inhibitors6 (described in the preceding paper)provided us with a working understanding of the structuralrequirements for JNK potency as well as kinase selectivity(Fig. 1).2 In addition, the result of our previous efforts emphasizedthe necessity of a careful balance of physico-chemical properties inorder to identify potent, selective, safe, and orally-available JNKinhibitors for chronic diseases.

While combining optimized C2 and N9 substituents described inFigure 1 (see preceding paper) did result in an improvement in po-tency and biochemical selectivity, the series evolved into unfavor-

ll rights reserved.

: +1 858 795 4719.in Krenitsky).

able property space for oral exposure (high MW, LogP, and pKa). Inparticular, we had identified a number of potent analogs incorpo-rating basic amines at either C2 or N9 positions, designed to makehydrogen-bond interactions within the active site and improveaqueous solubility. However, the corresponding analogs demon-strated poor plasma levels when orally administered in rats, andgenerally displayed high iv clearance and volumes of distribution.7

Others have successfully improved plasma exposure of basic com-pounds by attenuating the pKa values.8 While our attempts to re-duce the basicity of aminopurine via acylation resulted in ananalog with maintained potency, no improvement in the oral PKprofile was observed. With these observations in mind, we adoptedthe following strategy to obtain potent JNK inhibitors with oralbioavailability. Firstly, we re-focused our designs toward sub-ser-ies with lower molecular weight and lipophilicity, and devoid ofbasic amine substituents. Secondly, in order to understand theparameters and issues affecting plasma exposure, we collectedrat PK data on a set of structurally diverse analogs.

Our objective to lower molecular weight led us to revisit ana-logs incorporating small C2 substituents (Fig. 1). An isopropylamine group provided a good fit for the lipophilic portion of thesolvent-exposed region, and enabled us to elaborate the N9 substit-utent while operating within reasonable ranges of molecularweight and lipophilicity. Selected results are highlighted inTable 1.9

We were initially quite interested in 2 due to favorable potency,oral exposure, and F%. However, metabolite identification studies

HN

O

HN

H2N OHO

ONR1

R2

N

NN

N

R9

R2

R8

Hydrophobic back pocket

Ribose-binding pocket

Solvent-exposed region

Hinge

NH

F

NH

F F

HN

HO

HN

Figure 1. Results of early SAR exploration for potency and selectivity

Table 1Optimization of R9 for oral exposure

N

NN

N

R8R9

HN

Compd 2 3 4 5

R8

NHF F

NHF F

F

NHF F

F

NHF F

F

R9

HO H2NO

HNO

NO

O

MW 402 447 487.5 517cLogD 3.06 3.06 3.75 3.19JNK1 IC50

a (lM) 0.16b 0.12b 0.079 ± 0.014 0.063 ± 0.012p38a IC50

a (lM) 0.91 0.16b 6.2b 6.4b

JNK cell lysate assay IC50a (lM) 0.5b 0.20b 0.2 0.23

Rat ivc CL (mL/min/kg) 20 25 31 26Rat pod AUC (lM�h) 22 5 4.7 2.4Rat % F 100 32 42 20Rat LPS–TNFa inhib. at 30 mpk NA 96% 92% 58%

a Average of two or more experiments.b Single experiment.c 2 mg/kg in 15% DMA/PEG.d Aqueous 0.5% CMC/0.25% Tween� 80.

1434 V. Plantevin Krenitsky et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1433–1438

performed on 2 revealed an in vivo hydroxylation of the C8 anilinesubstituent,10 suggesting the necessity to block this metabolic site.The replacement of the 2,4-difluoroanilinyl with a 2,4,6-trifluoroa-nilinyl group at C8 combined with the substitution of N9 hydrox-ycyclohexyl with bioisosteric cyclohexyl amides, led to synthesisand profiling of 3, 4, and 5. As compared with primary amide 3,

compounds 4 and 5 provided an improvement in JNK potency(JNK1 and JNK2/JNK311 data not shown) which translated to cellu-lar efficacy, and selectivity against p38a. With moderate rat ivclearance (31 and 26 mL/min/kg, for 4 and 5), oral bioavailabilitiesof 42.5% and 20% were observed respectively. These compoundsdemonstrated oral efficacy in an acute rat LPS-induced TNFa

Table 2PK profile comparison between analogs of 7

N

NN

N

NHR9

R2

F

F

Compd 6 7 8

R2

HN

H2N

HN

HO

HN

HO

R9

OMW 427.5 428.5 444.5cLogD 2.48 3.77 2.16JNK1 IC50

a(lM) 0.27 ± 0.031 0.12 0.39 ± 0.15p38a IC50

a (lM) 0.22 ± 0.078 0.56 2.7 ± 1.7JNK cell lysate assay IC50

a

(lM)0.35 ± 0.13 0.44 0.86 ± 0.62

Rat ivb CL (mL/min/kg) 66 59 21Rat poc AUC (lM�h) 0.36 2.7 12Rat F% 8 68 70

a Average of two or more experiments.b Single experiment.c 2 mg/kg in 15% DMA/PEG.d10 mg/kg in aqueous 0.5% CMC/0.25% Tween� 80.

Table 3R2 optimization

N

NN

N

NHR9

R2 F

Compd R9 R2 MW cLogD J

9

O

414 2.99 0

10

HN

OH

470 4.68 0

11 O

HN

OH

486 3.07 0

12O

HN

O

472 2.91 0

V. Plantevin Krenitsky et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1433–1438 1435

production model with a 92% and 58% inhibition of TNFa at30 mpk.12 With these results in hand, compounds 4 and 5 were se-lected for further profiling.

From the rat po PK data collected on several structurally diverseanalogs, we noted the following: (1) replacing the N9 cyclopentylsubstituent in 6 and 7 with a 4-tetrahydropyranyl substituent in8 resulted in a substantial decrease in rat iv clearance value (66and 59 vs 21 mL/min/kg) as well as an increase in rat plasma expo-sure upon oral administration as measured by rat po AUC (0.36 and2.7 vs 12 lM h, 70% rat oral bioavailability) (Table 2); (2) while lesspotent than 7, 8 showed a moderate increase in selectivity againstp38a. Consequently, 8 was deemed a promising starting point foradditional optimization.

We focused on improving potency and metabolic stability. Ef-forts to increase potency by optimizing the polar interactions be-tween the R2 substituents and the polar rim of the solvent-exposed region of the active site were unsuccessful and decreasedthe selectivity margin against p38a (Table 3).

We therefore turned our attention to the modification of the R9

substituent. As confirmed by the crystal structure of 8 in the JNK3active site (not shown),13 the N9 THP substituent does not makeinteractions that are optimal for potency. However, introducing achiral tetrahydrofuranyl moiety resulted in substantial improve-ments in potency and physico-chemical properties (see compound1, Table 4). While keeping the molecular weight low and maintain-ing cLogP below 2.5, the S-isomer, 1, was associated with a signif-icant improvement in JNK1 potency (IC50 = 0.061 lM) and cellularefficacy (IC50 = 0.20 lM). The improved potency (10-fold in theJNK1 assay) of 1 compared to the R-isomer, 16, was rationalizedby the crystal structure of 1 in the JNK3 active site (Fig. 2). TheS-isomer presents the oxygen of the THF substituent towardsAsn152 residue and makes a favorable electrostatic interaction

F

NK1 IC50a (lM) p38a IC50

a (lM) JNK cell lysate assay IC50a (lM)

.90 0.23 NA

.17b 0.29 1.8

.32 0.98 1.7

.54 >3.0 1.6

(continued on next page)

Table 3 (continued)

Compd R9 R2 MW cLogD JNK1 IC50a (lM) p38a IC50

a (lM) JNK cell lysate assay IC50a (lM)

13 O

HN

HNSOO

521 2.08 0.88 0.86 NA

14O

HN

HO

458 2.36 1.2 >3.0 2.5

15O

OH

472 2.61 1.3 >3.0 1.7

a Single experiment.b Average of two experiments.

Table 4Profile of N9 (S)-THF containing analogs

N

NN

N

NH

R2

O

F F

F*

Compd 16 1 17

R2

HN

HO

HN

HO

HN

OHN

R9

(R)

O

(S)

O

(S)

OMW 448 448 489cLogD 2.3 2.3 2.3JNK1 IC50

a (lM) 0.40 b 0.061 ± 0.024 0.051 ± 0.005JNK2 IC50

a (lM) 0.038 b 0.007 ± 0.002 0.010 ± 0.003JNK3 IC50

a (lM) 0.032 b 0.006 ± 0.002 0.007 ± 0.003p38a IC50

a (lM) >3.0 b 3.4 ± 1.1 4.2 b

JNK cell lysate assay IC50a

(lM)1.2 b 0.20 ± 0.060 0.091 ± 0.079

Rat iv c CL (mL/min/kg) NA 39 39Rat po d AUC (lM�h) NA 3.1 2.9Rat % F NA 30 33

a Average of two or more experiments.b Single experiment.c 2 mg/kg in solution consisting of 5% DMA and 30% PEG 400.d 10 mg/kg in aqueous 0.5% CMC/0.25% Tween� 80.

Figure 2. 14Crystal structure of 1 in JNK3 active site.15

Figure 3. Compound 1 docked in the p38a active site.16

1436 V. Plantevin Krenitsky et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1433–1438

with the side-chain NH2 of Asn152 whereas the R-isomer, 17, ori-ents the THF oxygen away from Asn152 and consequently cannotmake the same favorable interactions. The improved selectivityof 1 against p38a is rationalized by examination of the dockedstructure of the compound in the p38a active site (Fig. 3). TheTHF substituent binds in close proximity of residues Ser154 andAsp112 which provides a less favorable electrostatic environmentwhen compared to JNK (Asn152 and Ser193). The THF oxygen ori-ents itself towards Ser 154 backbone carbonyl which is less favor-able due to electrostatic repulsion.

Table 5Comparison of PK profile between 1 and 17 in multiple species

1 17

Species Rat Dog Monkey Rat Dog Monkeyiv 2 mg/kga 1 mg/kgb 1 mg/kgc 2 mg/kga 1 mg/kgb 1 mg/kgc

CL (mL/min/kg) 39 3.4 2.9 39 24 7.1Vss (L/kg) 1.7 1.5 1.6 2.5 1.4 0.8AUC (lM h) 1.9 11 13 1.8 1.4 4.7MRT (h) 0.7 7.3 10 1.1 1.0 1.8pod 10 mg/kg 10 mg/kg 10 mg/kg 10 mg/kg 10 mg/kg 10 mg/kgCmax (lM) 0.7 7.2 11 1.2 0.86 11Tmax (h) 1.5 2.5 1.3 0.7 0.67 0.83AUC (lM h) 3.1 86 100 2.9 3.3 23F % 30 27–93 77 33 24 48

a Solution consisting of 5% DMA and 30% PEG 400.b Solution 5% DMA, 30% PEG 400 and 65% isotonic 50 mM citrate buffer (pH 5.0).c Solution consisting of 5% DMA and 95% isotonic citrate buffer (50 mM, pH 5.0).d In aqueous 0.5% CMC/0.25% Tween� 80.

V. Plantevin Krenitsky et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1433–1438 1437

Compound 1 was cleared rapidly in the rat (39 mL/min/kg). Usingin vitro metabolite identification studies, the major metabolite in ratwas shown to stem from the isomerization of the C2 hydrox-ycyclohexyl substituent, a process that may be mediated by oxidore-ductases17 and also previously observed with 8. In vitro hepatocytestudies suggested that this isomerization is a species-dependentphenomenon.18 Whereas isomerization after 2 h of incubation inhepatocytes was major in rats and mice, only a trace amount was de-tected in dogs, monkeys, and humans. Since in rodents, the in vivoformation of the cis isomer tracked with in vitro observations, wehypothesized that this interconversion may be only minor or absentin higher species including humans.19 Therefore, compound 1 wasselected for further profiling studies. As a contingency plan, effortswere also directed to identify a suitable replacement for the C2

hydroxycyclohexyl group in 1. Among all substituents examined,trans-aminocyclohexylcarboxamides provided a comparable fit inthe solvent-exposed region of the JNK3 active site, and no evidenceof epimerization was observed in vitro or in vivo. Amide 17 met allpreliminary program criteria of potency against JNK1 and JNK2,selectivity against p38a, rat iv clearance and oral exposure, and thuswas also selected for further profiling studies.

Four compounds, 4, 5, 1, and 17, were therefore selected for fur-ther evaluation. Because compound 4 showed only moderate bio-availability in the dog (20%), it was dropped from consideration.Based on high individual animal variability in the oral dog PK pro-file and a 59% inhibition at 10 lM in the hERG patch-clamp assay,compound 5 was also deprioritized.

Compound 1 showed a superior overall PK profile compared to17 (summarized in Table 5). While moderate results were obtainedin dog for both compounds (variability and % F), the bioavailabilityof 1 in cynomolgus monkey was superior to that of 17 (77% vs48%). The C2 hydroxycylohexyl isomerization for 1 was below thelimits of detection in dog hepatocytes and tracked with a 1.5% for-mation in vivo (percentage calculated in vivo based on the po AUC).Similarly, trace isomerization in monkey hepatocytes translated intrace formation in vivo. This preliminary profiling highlighted thesuperiority of 1 over 17.

Compound 1 has favorable physico-chemical properties withMW = 448, LogD = 1.93, and pKa = 5.47. Solubility measured insimulated intestinal fluid was found to be 780 lg/mL. Compound1 was shown to be kinetically competitive with ATP in the JNK-dependent phosphorylation of the protein substrate c-Jun andpotent against all isoforms of JNK (Ki(JNK1) = 44 ± 3 nM,IC50(JNK1) = 61 nM, Ki(JNK2) = 6.2 ± 0.6 nM, IC50(JNK2) = 5 nM,IC50(JNK3) = 5 nM) and selective against MAP kinases ERK1 andp38a with IC50 of 0.48 and 3.4 lM respectively. Compound 1 alsoinhibits the formation of phospho-cJun in human PBMC stimulatedby phorbol-12-myristate-13-acetate and phytohemeagglutinin

(IC50 = 1 lM). Compound 1 showed remarkable selectivity in a pa-nel of 240 kinases, EGFR being the only non-MAP kinase inhibitedmore than 50% at 3 lM (IC50 = 0.38 lM). It inhibited no receptor atgreater than 50% at 10 lM concentration in a panel of 75 receptors,ion channels and neurotransmitter transporters. Finally, whentested against 22 diverse non-kinase enzymes at 10 lM, no inhibi-tion greater than 50% was observed.

The in vivo efficacy of 1 was assessed in multiple animal mod-els. In the acute rat LPS-induced TNFa production PK-PD model,the compound inhibited the production of TNFa by 23% and 77%at 10 and 30 mg/kg oral dose respectively.16 A mouse bleomycin-induced pulmonary fibrosis model, model of lung inflammationand fibrosis, was chosen to demonstrate chronic efficacy.16 Com-pound 1 was tested prophylactically at 25, 50, 100 and 150 mg/kg prior to instillation of bleomycin, followed by 13 days of b.i.d.dosing. A statistically significant inhibition of white blood cells,monocytes and lymphocytes was observed in the bronchoalveolarlavage at all doses compared to the vehicle control. Lung fibrosisscores were reduced by 18–32% in dose dependant manner.

Compound 1 does not inhibit CYP P450 enzymes significantlyand is metabolized by CYP 3A4 and 2D6. In vitro toxicity assaysshowed negative results in the AMES assay and only 8% inhibitionon the hERG patch-clamp assay at 10 lM. Moreover, a four-daysafety assessment (male rats dosed once daily for 4 days by oral ga-vage with suspensions of 1 in aqueous CMC at 30, 90 and 300 mg/kg) demonstrated no adverse observations or histological findingsat or below 90 mg/kg. Based on these results, 1 was selected as adevelopment candidate.

In summary, we described here the optimization of an amino-purine series of JNK inhibitors for oral administration. Strategicexploration of the SAR led to the identification of four structurallydiverse, selective, and orally active inhibitors. Based on its overallprofile, 1 (CC-930) has advanced to clinical development. Prelimin-ary results from dosing studies in healthy male volunteers haveindicated that CC-930 is well-tolerated and exposure is dose-pro-portional.20 A phase II clinical trial was initiated in January 2011to characterize the safety, pharmacokinetics, and biological activityof CC-930 in patients with idiopathic pulmonary fibrosis.21

Acknowledgement

The authors thank Dr. Nancy Delaet for her feedback on the con-tent of this Letter.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.bmcl.2011.12.027.

1438 V. Plantevin Krenitsky et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1433–1438

References and notes

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2. Raghu, G.; Collard, H. R.; Egan, J. J.; Martinez, F. J.; Behr, J.; Brown, K. K.; Colby, T.V.; Cordier, J.-F.; Flaherty, K. R.; Lasky, J. A.; Lynch, D. A.; Ryu, J. H.; Swigris, J. J.;Wells, A. U.; Ancochea, J.; Bouros, D.; Carvalho, C.; Costabel, U.; Ebina, M.;Hansell, D. M.; Johkoh, T.; Kim, D. S.; King, T. E., Jr.; Kondoh, Y.; Myers, F.;Müller, N. L.; Nicholson, A. G.; Richeldi, L.; Selman, M.; Dudden, R. F.; Griss, B.S.; Protzko, S. L.; Schünemann, H. L. Am. J. Respir. Crit. Care Med. 2011, 183, 788.

3. Plantevin Krenitsky, V.; Nadolny, L.; Sahasrabudhe, K.; Ayala, L.; Delgado, M.;Clareen, S.; Hilgraf, R.; Albers, R.; Kois, A.; Hughes, K.; Wright, J.; Sudbeck, E.;Ghosh, S.; Nowakowski, J.; Muir, J.; Cathers, B.; Giegel, D.; Xu, L.; Celeridad, M.;Moghaddam, M.; Khatsenko, O.; Omholt, P.; Pai, S.; Fan, R.; Tang, Y.; Shirley, M.A.; Benis, B.; Blease, K.; Raymon, H.; Bhagwat, S.; Henderson, I.; Cole, A. G.;Bennett, B.; Satoh, Y. Preceding article.

4. Tanemura, S.; Yamasaki, T.; Katada, T.; Nishina, H. Curr. Enz. Inhib. 2010, 6, 26.5. (a) Eynott, P. R.; Nath, P.; Leung, S.-Y.; Adcock, I. M.; Bennett, B. L.; Chung, K. F.

Br. J. Pharmacol. 2003, 140, 1373; (b) de Borst, M. H.; Prakash, J.; Sandovici, M.;Klok, P. A.; Hamming, I.; Kok, R. J.; Navis, G.; van Goor, H. J. Pharmacol. Exp. Ther.2009, 331, 896; (c) Kluwe, J.; Pradere, J.-P.; Gwak, G.-Y.; Mencin, A.; De Minicis,S.; Osterreicher, C. H.; Colmenero, J.; Bataller, R.; Schwabe, R. F.Gastroenterology 2010, 138, 347; (d) Wu, W.; Muchir, A.; Shan, J.; Bonne, G.;Worman, Howard J. Circulation 2011, 123, 53; (e) De Borst, M. H.; Prakash, J.;Melenhorst, W. B. W. H.; van den Heuvel, M. C.; Kok, R. J.; Navis, G.; van Goor,H. J. Pathol. 2007, 213, 219.

6. Siddiqui, M. A.; Reddy, P. A. J. Med. Chem. 2010, 53, 3005.7. Of 29 compounds containing at least one basic amine and tested in rat iv PK

(2 mg/kg), 23 analogs showed a combination of high CL (>60 mL/min/kg) andhigh Vss (>7 L/kg). See also (a) Smith, D. A.; Jones, B. C.; Walker, D. K. Med. Res.Rev. 1996, 16, 243; (b) Gleeson, M. P. J. Med. Chem. 2008, 51, 817.

8. Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R. E.;Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.;Diederich, F.; Kansy, M.; Müller, K. ChemMedChem 2007, 2, 1100.

9. Experimental details on biochemical and cellular assays can be found in theSupplementary data section.

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11. This class of compounds is 8–10 times more potent in JNK2 and JNK3 thanJNK1.

12. Model for the assessment of the potential anti-inflammatory effects oftherapeutic agents on acute cytokine production by measuring the effect of acompound administered by oral gavage, on the release of plasma tumornecrosis factor (TNF)-a following lipopolysaccharide (LPS) injection. SeeSupplementary data for details.

13. The JNK3 isoform was the only one available to us for crystallography duringthis drug discovery program.

14. All images were generated using using The PyMOL Molecular Graphics System,Version 1.3, Schrödinger, LLC.

15. The PDB deposition code for 1 JNK3 complex crystal structure is 3TTI.16. See Supplementary data for details.17. Davies, N. M. In Chiral Inversion; Reddy, Mehvar, Eds.; Chirality and Drug

Design and Development; Marcel Dekker Inc.: New York, 2004; pp 351–392.Chapter 8.

18. A similar trend was observed prior to the profiling of 1 with compoundscontaining cis-hydroxy cyclohexyl amine at the C2 position. See also: Chu-Moyer, M. Y.; Ballinger, W. E.; Beebe, D. A.; Coutcher, J. B.; Day, W. W.; Li, J.;Oates, P. J.; Weekly, R. M. Bioorg. Med. Chem. Lett. 2002, 12, 1477.

19. The percentage of the cis isomer was calculated in vivo based on the po AUC.The major isomerization in mouse and rat hepatocytes translated in the in vivoformation of 20% and 200%, respectively of the cis isomer. On the other hand,the isomerization in dog was below limit of detection in vitro and tracked witha 1.5% formation in vivo. Trace isomerization in monkey resulted in traceformation in vivo as well. A similar profile was observed with analogscontaining a trans-hydroxy cyclohexyl amine at C2.

20. Ye, Y.; Kong, L.; Assaf, M.; Liu, L.; Wu, A.; Lau, H.; Choudhury, S.; Laskin, O. Clin.Pharmacol. Ther. 2011, 89, 31.

21. www.clinicaltrials.gov; Trial Identifier NCT01203943.

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