Wivol. 7 No. 1
`
`7 January 1997
`
`_ISSN 0960-894X
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`A Tetrahedron Publication
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`

`
`Tetralzectron Prize for Creativity in Organic Chemistry
`Contributors to this Issue
`
`Graphical Abstracts
`Synthesis and evaluation of the anticonvulsant activity of a series of 2-samino.
`1-phenyl-1-propanols derived from the metabolites of the antidepressant
`bupropion
`Bis-quinoliialum cycloplianes: a novel class of potent blockers of the apamin-
`sensitive Caz’-activated K* channel
`
`Studies on penam sultones—l|l. Synthesis and 1'3-Iactamase inhibitory activity
`of
`sodium (6Fl)-6-(oi-hydroxybenzy|)—2B-methoxyiminomethyi-2oz-2*iethyl-
`penam-Soi-carboxylate 1,1-dioxide and sodium 2B-acyl-2oz-methylpenam-3cx-
`carbcxylate 1 ,1-dioxide
`
`Bleomycin model complex bearing a carbamoyl derived substituent capable
`of coordination to the chelated metal ion as a sixth ligand
`
`SAR for MHC class I! binding tetrapeptides: correlation with potential binding"
`site
`
`25
`
`31
`
`37
`
`47
`
`The synthesis and biological activity of some Known and putative meieooliles
`of the atypical antipsychotic agent olanzapine (LY170053)
`
`2,3-Substituted 2-azanorbornanes as polar B-turn mimetics
`
`Structure—activity studies of CTL inhibitory peptides derived from HL»“ class
`I molecules
`
`,
`
`ct-((Tetronoy|)oxy)- and oi-((tetramoyi)oxy)methyl ketone inhibitors of the I
`interleukin-1B converting enzyme (ICE)
`
`Synthesis and biolo ical evaluation of 5,6-diarylimidazo[2.*.—b]thia2o|e as f
`selective COX-2 inhi
`itors
`
`V
`
`*
`
`D. L.
`lillusso. N. B. Mehta and
`F. E. Soroko
`
`C. . Campos Rosa,
`. M. Beckwith-Hall, D. Galanakis,
`. R. Ganellin, P. M. Dunn and
`. H. Jenkinson
`
`. P. Czajkowski, A. V. N. Fte<£«.l\_.',
`. L. Setti, O. A. Phillips,
`. G. Micetich, C. Kunugita and
`. N. Haiti
`
`. Aral, K. Shinozuka and H. Sawai
`
`-I(DIITIUUOW
`>i"l'TiflW
`U-ID
`0'11IO
`2:I-=m:>—IL . A. Cromlish, J. Y. Gauthier,
`
`. R. Cunningham, M. Fllvetna,
`. L. Toiman, S. J. Flattery,
`. A. Nichols, C. D. Schwartz,
`. S. Wicker, J. D. Hermes and
`. B. Jones
`
`. 0. Calligaro, J. Falrhurst,
`. M. Hdtten, N. A. Moore and
`. E. Tupper
`. C. Horwell, D. it-iaylor and
`. M. G. Willeins
`
`_. J. Schwartz, J. Goldberg,
`. Claybergeir, A. M. Krensky and
`. H. Griffin
`
`. L Graybill, C. P. Prouty,
`J. Speier, D. Hoyer, R. E. Dolle,
`T. Helaszek, M. A. Ator, J. Uhl
`nd J. Strasters
`
`. Thérien, C. Brideau, C. C. Chan.
`
`. Gordon. G. Greig, S. Kargman.
`. K. Lau, Y. Leblanc, C.-S. Ll,
`. P. O’Nei|l, D. Riencleau, P. Roy,
`. Wang, L. Xu and P. Prasit
`
`N003!
`
`_l
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`|lll||l|llllllllllllllllllll
`
`0960-89/iX(‘l997)7: ‘I ; ‘l -I
`
`[Continued on inside baci. covef]
`
`
`
`L§i3Ril~‘aRY'
`
`Indexed/Abstracted in: Chemical Abstracts, Current Contents,
`Science Citation Index, Scisearch, Research Alert, Excerpta Medica
`Database EMBASE, CABS (Current Awareness in Biological Sciences)
`
`BMCLE8 7(1) 1-98 (1997)
`
`Pergamon
`
`‘.3/Z
`
`Printed in Great Britain by Nuffield Press Ltd.
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`

`
`Bioorganic & Medicinal Chemistry Letters Vol. 7, No. 1, 1997
`'
`
`contents [Continued from outside back cover]
`
`_ Roy, Y. Leblanc, R. G. Ball,
`_Brideau, C. C. Chan, N. Chauret,
`w, Cromlish, D. Ethier,
`J, Y. Gauthier, R. Gordon, G. Grelg,
`J. Guay, S. Kargman, C. l,(..Lau,
`G_ o'Ne|||, J. Silva, M. Therren,
`c. van Staden, E. Wong, L. Xu and
`P. Prasit
`S. Routier, J.-L. Bernier,
`J,-P. Catteau and C. Bailly
`
`RS
`
`JAw
`
`53
`
`57
`
`63
`
`67
`
`73
`
`79
`
`85
`
`89
`
`95
`
`Characterization of the in vitro oxidative metabolites of the COX-2 selective
`inhibitor L-766,112
`,
`
`A new series of selective COX-2 inhibitors: 5,6-diaryllhiazolo[3,2-b][1.2,4]-
`triazoles
`
`Highly preferential cleavage of unpaired guanines in DNA by a functionalized
`sa|en—nickel complex
`
`Synthesis, evaluation, and crystallographic analysis of L-371,912: a potent
`and selective active-site thrombin inhibitor
`
`Phosphorothioate oligonucleotides: largely reduced (n -1 )-mer and phospho-
`diester content through the use of dimerlc phosphoramidite synthons
`S, heterocyclic thrombin inhibitors
`
`Synthesis and hepatoprotective effects of soyasapogenol B derivatives
`
`lmidazotriazinone inhibitors of
`diesterase (PDE I)
`
`the Ca“-calmodulin sensitive phospho-
`
`Combinatorial epitope search: pitfalls of library design
`Instructions to Contributors
`
`Aims & Scope
`
`1-_ A, Lyle, Z. Chen, S. D. Appleby,
`. M. Freidinger, S. J. Gardell,
`.D. Lewis, Y. Li, E. A. Lyle,
`J. Lynch, Jr, A. M. Mulichak,
`_s. Ng, A. M. Naylor-Olsen and
`. M. Sanders
`A H. Krotz, P. Klopchin, D. L. Cole
`n V. T. Ftavikumar
`
`Dd
`
`ominguez, D. J. Carini,
`G. Weber, R. M. Knabb,
`5. Alexander, C. A. Kettner and
`Ft
`. Wexler
`
`Sasaki, N. Minowa, H. Kuzuhara,
`.Nishiyama and S. Omoto
`D. J. Hlasta, D. C. Bode, J. J. Court,
`R. C. Desai, E. D. Pagani and
`P. J. Silver
`
`2. Yu and Y.-H. Chu
`
`B CPRR KS
`
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`
`This material may he pmteaea by Copyright law [Title 17 us. Cede]
`
` Pergarnon
`
`Biuozgaiiic & M:-rlirinal Cl1emi'sIij\* [4l‘ll(‘l‘_\', Vol. 7, No.
`
`l, pp. 79-84. I997
`
`PH. S0960 894X(96)O0584_7
`
`Printed in Great Britain. All rights reserved
`
`Copyright © 1996 Elsevier Science Ltd
`0960—894X/97 $17.00 + 0.00
`
`S, HETEROCYCLIC THROMBIN INHIBITORS
`
`C. Dominguez,* D. J. Carini, P.C. Weber,‘ R. M. Knabb,
`R. S. Alexander, C. A. Kettner, and R. R. Wexler.
`
`DuPont Merck Pharrna.cem‘ica.l Company, Experimental Station,
`P. 0. Box 80500, Wilmington, DE 19880-0500.
`
`Abstract: A series of boropeptides have previously been described by Kettner et al. to be potent thrombin
`inhibitors. DuP 714 is a representative of this class of compounds with a K = 0.040 nM, but this inhibitor has
`undcsit‘eable side effects. New and selective boronic acid thrombin inhibitors have been developed by replacing
`the guanidine of the boroarginine side chain with various heterocycles ranging in size and basieity.
`Copyright © I996 Elsevier Science Ltd
`
`Thrombin is involved in the pathogenesis of thrombosis. It functions as the last protease in the blood
`
`coagulation cascade hydrolyzing fibrinogen to insoluble fibrin? Boropeptides are highly effective inhibitors of
`
`thrombin.3 DuP 714, Ae—(D)—Phe-Pro—boroArg—OH,
`
`is effective in preventing both venous and arterial
`
`thrombosis} but it has a low margin of safety. DuP 714 has a K, of 0.040 nM for thrombin and is two orders of
`
`magnitude less reactive with other plasma proteases. However,
`
`it readily inhibits trypsin and it
`
`is our
`
`expectation that compounds with greater selectivity will provide safer inhibitors.
`
`X—ray crystal structures of thrombin and trypsin revealed that the thrombin P, pocket is slightly larger
`
`than that of trypsin. The Serm in trypsin narrows the P, pocket (Figure 1). We envisioned utilizing the pocket
`
`size differences between thrombin and trypsin to obtain selectivity over trypsin and other relevant serine
`
`proteascs. We also wanted to explore the possibility of decreasing the basicity of the guanidine group of DuP
`
`714 with various heterocycles as the literature suggests that increased toxicity may be attributed to highly basic
`
`functionalitiesf‘ Herein, we report selective 5- and 6—membered heterocycles ranging in size and basicity. and
`
`the identification of the butanesulfonamide as a potent replacement of the acetamide group in DuP 714.
`
`DuP 714
`
`” VG
`NHAC
`Thrombin K, = 0.040 nM
`N
`FXa Ki = 9.0 nM
`Trypsin K; = 0.045 nM
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`
`80
`
`C. DOMINGUEZ er al.
`
`Figure 1. Supcrimposition of the S1 Pockets of Thrombin and Trypsin.
`
`Figure 2. Co—crysta1 structure of Compound 1 in Thrombin.
`
`
`
`
`Replacing the guanidine group of DuP 714 with a heterocycle provided selectivity over trypsin and FX21
`
`(Table 1, compound 2). However we lost inhibitory potency against thrombin compared to DuP 714. We also
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`
`S] heterocyclic thrombin inhibitors
`
`81
`
`observed that the butanesulfonamide derivative 2 greatly increased the inhibitory affinity for thrombin
`Compared to the acetyl derivative 1. Modeling of derivative 2 in the thrombin active site suggests that the
`increase in affinity is due to the longer bond length of the sulfonamidc bond which allows one of the
`
`sulfonainide oxygens to form a H-bond with the NH of Glym.
`
`Table 1. S, 6-Membered Heteroeyelie Thrombin Inhibitors
`
`NH
`
`O
`
`O
`
`N
`
`NHR1
`
`Ki(nM)
`
`No
`R2
`R,
`Thrombin
`Trypsin
`FXa*
`
`Cl
`
`HQN
`
`I
`
`11/
`J\~
`N
`Cl
`
`\
`NH
`
`Ac
`
`N’ I
`is
`N
`
`HZN
`
`‘.
`N ~H
`
`SO2Bu
`
`43
`
`2.1
`
`>120o
`
`>6000
`
`214
`
`>6000
`
`Ac
`
`Ae
`
`Ac
`
`Ac
`
`150
`
`ND
`
`ND
`
`230
`
`>120o
`
`>oo00
`
`2000
`
`>1200
`
`ND
`
`600
`
`>12oo
`
`>eoo0
`
`N’ I
`N
`Js
`
`HZN
`
`N *H
`~
`
`NH
`
`\;
`
`” 1
`N
`~
`
`/ N
`
`sN J\ F\.\:
`/ N
`
`~N 1 NB;
`II
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`61
`8.8
`S0281]
`~NJ\o~,;
`7
`ND : Not determined. The K,’s were determined as described by Kettner et al.“
`*l’Xa is another serine protease involved in the coagulation cascade.”
`
`ND
`
`ND
`
`Co—crystallization of compound 1 in thrombin also revealed that the pyrimidine ring was only in the Pl
`Specificity pocket 50% of the time (Figure 2) and yet we obtained nanomolar K1 affinity for thrombinxl The X-
`
`ray structure of 1 may explain why the thiol analog 5 was not as potent as arninopyrimidine 6. The loss in
`P0f€I1Cy of compound 5 is probably due to the longer sulfur bond in the thiopyrimidine, which may not be
`"accommodated in the P, specificity pocket. Pyrimitline 7 clearly exemplifies how vital the butanesulfonarnide
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`
`82
`
`C. DOMINGUEZ Gt (1/.
`
`group is to increasing thrombin inhibition compared to acetamide group in compound 5. Interestingly, 2.
`
`aminopyrimidine 3 lost 25-fold affinity for thrombin compared to compound 1 and the pyridine derivative 4
`
`also lost affinity for thrombin compared to 3, suggesting that the chlorine atom of compound 1 and the 2-amino
`
`group of compound 1 and 3 must play a role in the binding.
`
`Table 2. S. 5—Membered Heterocyclic Thrombin Inhibitors
`
`K. (nM)
`
`No.
`R,
`R,
`Thrombin
`Trypsin
`FXa
`
`8
`
`9
`
`10
`
`1 1
`
`12
`
`13
`
`14
`
`(\ Njf
`N =/
`NH2
`
`%\ N‘):
`N =/
`NH2
`
`(\ N}:
`Na
`N02
`
`Y/\Nj\:
`N =1
`N02
`
`/ N Z~’
`N=/
`
`N _
`
`N02
`
`)1) ~ .
`g_ NH
`NH2
`
`Ac
`
`SO3Bu
`
`SO2Bu
`
`Ac
`
`Ac
`
`Ac
`
`Ac
`
`1.7
`
`3.2
`
`15
`
`20
`
`40
`
`>6000
`
`970
`
`>1200
`
`6000
`
`650
`
`>1200
`
`>6000
`
`67
`
`199
`
`507
`
`27
`
`6000
`
`>l20O
`
`>6000
`
`>1200
`
`>6000
`
`6000
`5
`N5N/“$5
`>1 200
`Ac
`15
`3. 0
`N =<
`NH2
`
`Table 2 illustrates representative examples of the 5-membered S, heterocyclic thrombin inhibitors. The
`
`2—aminoimidazo1e analogs proved to be the most potent of this series even though X—ray results suggest that the
`
`amino group does not interact with Aspm. These compounds demonstrate that we were indeed able to Obtain
`
`potent and selective thrombin inhibitors with a less basic P, group.
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`St hetcrocyclic thrombin inhibitors
`
`83
`
`The 2-nitroimidazole analog 10 (Table 2) also exhibited good affinity for thrombin and excellent
`
`selectivity over trypsin and FXa. Here again the butanesulfonamide group greatly increased the affinity for
`
`[hrornbin compared to the acetamide group (11). The nitro group probably plays a key role in the selectivity
`
`over trypsin due the size of the 2-nitroirnidazole versus the smaller size of the S1 pocket of trypsin. This is in
`
`contrast to the smaller imidazole compound (12), which shows no selectivity over trypsin.
`
`The more acidic heterocycles, such as the triazoles (13 and 14), and the tetrazole (15) did not exhibit the
`
`game affinity for thrombin as the irnidazole analogs. Presumably the more basic the P] group, the stronger the
`
`interaction with Asp” in the specificity pocket of thrombin.
`
`Chemistry
`
`All the guanidine replacements were prepared from the ot—aminoboronic acid 16, which is obtained via
`
`Matteson chernistIy."" Peptide coupling with isobutylchlorofoririate (IBCF), N—methylm0rpholir1e (NMM), and
`
`triethylamine in THF at 0 °C gave intermediate 17. Compounds 5, 6, and 8-15 were prepared Via alkylation of
`
`intermediate 17 with the appropriate heterocyclcs.7
`
`The 2.-aminopyrirnidin-6—yl compounds were prepared Via the ornithine intermediate by azide formation
`
`followed by catalytic hydrogenation and chlorine displacement.
`
`Synthesis
`
`NH2 - HCl
`
`a
`j>
`
`N“
`
`0
`
`O
`
`NH
`
`O
`
`’\I
`
`NHR1
`
`19
`
`NH
`
`O
`
`O
`
`NHR1
`
`18
`
`Ifeagemsz (21) IBCF, NMM, R,(D)Phe—Pro—OH, Et,N, 0 0c, 85%; (b) NaN1, DMF, 80%; (e) H2, Pd(OH)3/C, I-ICI; 90% (d)
`E’tlN> DMF, R,—C1, 60 °C, 50-60%; (e) R,—H, DMF, K2CO3, 60 °c, 60%.
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`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2133 - 9/10
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`

`
`84
`
`C. DOMINGUE7. er al.
`
`Conclusion
`
`By manipulating the size and basicity of guanidine replacements potent and selective thrombin
`
`inhibitors (2, 8, and 9) have been obtained. Additionally the N—butanesulfonan1ide group has been identified as
`
`a potent replacement for the N—acety1 group of DuP 714. Although the affinity of these compounds is decreased
`
`compared to DuP 714, they are more selective for thrombin over other serinc proteases.
`
`Acknowledgements
`
`We wish to thank J. M. Luettgen, L. J. Mersinger, and S. Spitz for obtaining compound binding data.
`
`References and Notes
`
`1.
`
`2.
`
`11-)
`
`Current address: Schering Plough Research lnstitutc, 2015 Galloping Hill Road, Kenilworth, NJ. 07033,
`
`Knabb, R. M.; Kettner, C. A.', Timmermans, P. B. W. M.; Reilly, T. M. Thromb. Haem0stasi's 1992,
`
`67. 56.
`
`(a) Kettner, C. A; Mersinger, L.: Knabb, R.
`
`.1. Biol. Chem. 1990, 265, 18289. (b) Radcliffe, R.;
`
`Neinerson, Y. In Mel/z0u'.\' in Enzymologyg Lorand, L., Ed; Academic: London, 1976, Vol XLV, p 49.
`
`4.
`
`(a) Okamoto, S.; Hijikata, A. Biochim. Biophys. Res. Commun. 1981, 101, 440. (b) Hifijikata-
`
`Okunomiya, A.; Okamoto, S. Thromb. Haemostasis 1992, I8, 135. (c) Angliker, H.; Wilstrom, l’.;
`
`Shaw, E. Biochim J. 1990, 266, 829.
`
`(C1) Elgendy, S.; Deadman, J.; Patel, G.; Green, D.; Chino. NJ.
`
`Goodwin, C. A.; Scully, M. F.; Kakkar, V. V.; Claeson, G. Tetrahedron Len‘. 1992, 33, 4209. (e) Misra.
`
`R. N.; Kelly, Y. K.; Brown, B. R.', Roberts, D. G. G. M.; Chong, S.; Seiler, S. M. Bioorg. Med. Chem-
`
`Lett. 1994, 4, 2165.
`
`U1
`
`6.
`
`7.
`
`Data were refined to 2.3 A resolution and the structure refined to an Rmor 0.21 1.
`
`Matteson, D. S.; Jeshi, P. K,; Sadha, K. M. Organamezallics 1984, 3, 1284.
`
`Satisfactory spectral data were obtained for all new compounds.
`
`(Received in USA 31 Orrtober 1996; accepted 25 November 1996)
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`CFAD v. Anacor, |PR2015—O1776 ANACOR EX. 2133 — 10/10
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