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`JOURNAL OF
`
`EDICINAL®
`CHEMISTRY
`
`Registered in U.S. Patent and Trademark Office
`© Copyright 1992 by the American Chemical Society
`
`Volume 35, Number 18
`September 4, 1992
`
`JMCMAR 35(18) 3307-3428 (1992)
`ISSN 0022-2623
`
`COMMUNICATIONS TO THE EDITOR
`
`3-Phenyl-4-hydroxyquinolin-2(1H)-ones: Potent and Selective Antagonists at the Strychnine—Insensitive Glycine Site on
`the N-Methyl-D-aspartate Receptor Complex
`Loretta A. McQuaid,* Edward C. R. Smith, David Lodge, Etienne Pr-along, James H. Wikel,
`David O. Calligaro, and Patrick J. O’Malley
`
`Specific Inhibition of HIV-1 Protease by Boronated Porphyrins
`Dianne L. DeCamp, Lilia M. Babé, Rafael Salto, Jeanne L. Lucich, Myoung-Seo Koo, Stephen B. Kahl,* and
`Charles S. Craik*
`
`ARTICLES
`
`Novel 5-HT3 Antagonists. Isoquinolinones and 3-Aryl-2-pyridones
`Toshiaki Matsui, Tsuneyuki Sugiura, Hisao Nakai,* Sadahiko Iguchi, Satoshi Shigeoka, Hideo Takada,
`Yoshihiko Odagaki, Yuhki Nagao, Yasuyuki Ushio, Kazuyuki Ohmoto, Hiroyuki Iwamura,
`Shinichi Yamazaki, Yoshinobu Arai, and Masanori Kawamura
`Synthesis and Excitatory Amino Acid Pharmacology of a Series of Heterocyclic-Fused Quinoxalinones and Quinazolinones
`Loretta A. McQuaid,* Edward C. R. Smith, Kimberly K. South, Charles H. Mitch, Darryle D. Schoepp,
`Rebecca A. True, David O. Calligaro, Patrick J. 0’Malley, David Lodge, and Paul L. Ornstein
`
`Synthesis and Pharmacological Studies of N-Substituted
`6-[(2-Aminoethyl)amino]-1,3-dimethyl-2,4(1H,3H)—pyrimidinediones, Novel Class III Antiarrhythmic Agents
`Tsutomu Katakami,* Tatsuro Yokoyama, Michihiko Miyamoto, Haruki Mori, Nobuya Kawauchi,
`Tadahito Nobori, Kunio San—nohe, Tatsuo Kaiho,* and Joji Kamiya
`Synthesis of a Homologous Series of Ketomethylene Arginyl Pseudodipeptides and Application to Low Molecular Weight
`Hirudin—like Thrombin Inhibitors
`John DiMaio,* Bernard Gibbs, Jean Lefebvre, Yasuo Konishi, Debra Munn, Shi Yi Yue, and
`Wilfried I-Iornberger
`
`Determination of the Absolute Configuration of the Active Amlodipine Enantiomer as (-)-S: A Correction
`Siegfried Goldmann,* Jiirgen Stoltefuss, and Liborius Born
`Synthesis and Functional Evaluation of a Peptide Derivative of 1-3-D-Arabinofuranosylcytosine
`Zoltfin Balajthy,* Janos Aradi, Ildiké T. Kiss, and P211 Eliidi
`cis-Bis(pyridine)platinum(II) Organoamides with Unexpected Growth Inhibition Properties and Antitumor Activity
`Lorraine K. Webster,* Glen B. Deacon,* David P. Buxton, Brian L. Hillcoat, Alison M. James,
`Ian A. G. Boos, Robin J. Thomson, Laurence P. G. Wakelin, and Tracey L. Williams
`
`Synthesis and Antibronchospastic Activity of 8-Alkoxy- and 8-(Alkylamino)imidazo[L2-a]pyrazines
`Pierre A. Bonnet, Alain Michel, Florence Laurent, Claire Sablayrolles, Eliane Rechencq, Jean C. Mani,
`Maurice Boucard, and Jean P. Chapat*
`Synthesis and Chemical Characterization of N-Substituted Phenoxazines Directed toward Reversing Vinca Alkaloid
`Resistance in Multidrug-Resistant Cancer Cells
`Kuntebommanahalli N. Thimmaiah, Julie K. Horton, Ramakrishnan Seshadri, Mervyn Israel,
`Janet A. Houghton, Franklin C. Harwood, and Peter J. Houghton*
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2128 - 3/7
`
`

`
`Journal of Medicinal Chemistry, 1992, Vol. 35, No. 18 5A
`
`e Pseudopeptide Analogues as Thrombin Inhibitors
`Michael F. Schully, Vijay V. Kakkar, and Goran Claeson*
`
`Synthesis and Biological Activity of Ketomethylen
`Leifeng Cheng,* Christopher A. Goodwin,
`Anti-HIV Activity to 3’-Fluor0—3’—deoxythymidine
`Erik De Clercq, Jan Balzarini, and Daniel J. Swartling
`
`3’,3’—Difluoro-3’-deoxythymidine: Comparison of
`Donald E. Bergstrom,* Andrew W. Mott,
`Synthesis and Antiviral Properties of (i)-5’-Noraristeromycin and Related Purine Carbocyclic Nucleosides. A New Lead
`for Anti-Human Cytomegalovirus Agent Design
`ki Hosoya, Robert Snoeck, Graciela Andrei,
`Sharadbala D. Patil, Stewart W. Schneller,* Mitsua
`Jan Balzarini, and Erik De Clercq
`
`Antitumor Imidazotetrazines. 25. Crystal Structure of 8-Carbamoyl-3—methylimidazo[5,1-cl]-1,2,3,5-tetrazin-4(3H)-one
`omparisons with the Related Drugs Mitozolomide and DTIC
`(Temozolomide) and Structural C
`H. Schwalbe,* M. F. G. Stevens, and A. S. Clark
`P. R. Lowe, C. E. Sansom, C.
`
`Energy Aspects of Oil/Water Partition Leading to the Novel Hydrophobic Parameters for the Analysis of Quantitative
`Structure—Activity Relationships
`Yong-Zhong Da, Katsuhilgo Ito, and Hideaki Fu]'iwara*
`Synthesis and Biological Evaluation of Dihydroeptastatin, a Novel Inhibitor of 3—Hydroxy-3-methylglutaryl
`Coenzyme A Reductase
`and Richard S. Todd
`Elisabeth A. Bone, Alan H. Davidson, Christopher N. Lewis,*
`
`Non-Prostanoid Thromboxane A2
`Receptor Antagonists with a Dibenzoxepin Ring System. 1
`Hiroyuki Obase,* Ichiro Miki, Akio Ishii, Akira Karasawa,
`Etsuo Ohshima, Hitoshi Takami, Hideyuki Sato,
`and Kazuhiro Kubo
`
`Non-Prostanoid Thromboxane A2 Receptor Antagonists with a Dibenzoxepin Ring System. 2
`Etsuo Ohshima, I-Iitoshi Takami, Hideyuki Sato, Shinichiro Mohri, Hiroyuki Obase,* Ichiro Mil-ri,
`Akio Ishii, Shiro Shirakura, Akira Karasawa, and Kazuhiro Kubo
`
`Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 3. 3-Substituted-4-(phenylamino)quino1ines
`Robert J. Ife,* Thomas H. Brown, David J. Keeling, Colin A. Leach, Malcolm L. Meeson,
`Michael E. Parsons, David R. Reavill, Colin J. Theobald, and Kenneth J. Wiggall
`
`I Supplementary material for this paper is available separately (consult the masthead page for ordering information); all
`supplementary material except structure factor tables will also appear following the paper in the microfilm edition of this
`journal.
`
`* In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper
`should be addressed.
`
`Andrei, G., 3372
`Aradi, J., 3344
`Arai, Y., 3307
`
`Babé, L. M., 3426
`Balajthy, Z., 3344
`Balzarini, J., 3369, 3372
`Bergstrom, D. E., 3369
`Bone, E. A., 3388
`Bonnet, P. A., 3353
`Born, L., 3341
`Boucard, M., 3353
`Brown, T. H., 3413
`Buxton, D. P., 3349
`
`Calligaro, D. 0., 3319,
`3423
`Chapat, J. P., 3353
`Cheng, L., 3364
`Claeson, G., 3364
`Clark, A. S., 3377
`Craik, C. S., 3426
`
`Eladi, P., 3344
`
`Fujiwara, H., 3382
`
`Gibbs, B., 3331
`Goldmann, S., 3341
`Goodwin, C. A., 3364
`
`Harwood, F. C., 3358
`Hillcoat, B. L., 3349
`Hornberger, W., 3331
`Horton, J. K., 3358
`Hosoya, M., 3372
`Houghton, J. A., 3358
`Houghton, P. J., 3358
`
`Ife, R. J., 3413
`Iguchi, S., 3307
`Ishii, A., 3394, 3402
`Israel, M., 3358
`Ito, K., 3382
`Iwamura, H., 3307
`
`James, A. M., 3349
`
`Da, Y.-Z., 3382
`Davidson, A. H., 3388
`Deacon, G. B., 3349
`DeCamp, D. L., 3426
`De Clercq, E., 3369, 3372
`DiMaio, J., 3331
`
`Kahl, S. B., 3426
`Kaiho, T., 3325
`Kakkar, V. V., 3364
`Kamiya, J., 3325
`Karasawa, A., 3394, 3402
`
`AUTHOR INDEX
`
`Katakami, T., 3325
`Kawamura, M., 3307
`Kawauchi, N., 3325
`Keeling, D. J., 3413
`Kiss, I. T., 3344
`Konishi, Y., 3331
`Koo, M.-S., 3426
`Kubo, K., 3394, 3402
`
`Laurent, F., 3353
`Leach, C. A., 3413
`Lefebvre, J., 3331
`Lewis, C. N., 3388
`Lodge, D., 3319, 3423
`Lowe, P. R., 3377
`Lucich, J. L., 3426
`
`Mani, J. C., 3353
`Matsui, T., 3307
`McQuaid, L. A., 3319,
`3423
`Meeson, M. L., 3413
`Michel, A., 3353
`Miki, 1., 3394, 3402
`Mitch, C. H., 3319
`Miyamoto, M., 3325
`Mohri, S., 3402
`Mori, H., 3325
`Mott, A. W., 3369
`Munn, D., 3331
`
`Nagao, Y., 3307
`Nakai, H., 3307
`Nobori, T., 3325
`
`Obase, H., 3394, 3402
`Odagaki, Y., 3307
`Ohmoto, K., 3307
`Ohshima, E., 3394, 3402
`O’Malley, P. J., 3319,
`3423
`Ornstein, P. L., 3319
`
`Parsons, M. E., 3413
`Patil, S. D., 3372
`Pralong, E., 3423
`
`Reavill, D. R., 3413
`Rechencq, E., 3353
`Roos, I. A. G., 3349
`
`Sablayrolles, C., 3353
`Salto, R., 3426
`San~nohe, K., 3325
`Sansom, C. E., 3377
`Sato, H., 3394, 3402
`Schneller, S. W., 3372
`Schoepp, D. D., 3319
`Schully, M. F., 3364
`Schwalbe, C. H., 3377
`Seshadri, R., 3358
`
`Shigeoka, S., 3307
`Shirakura, S., 3402
`Smith, E. C. R., 3319,
`3423
`Snoeck, R., 3372
`South, K. K., 3319
`Stevens, M. F. G., 3377
`Stoltefuss, J., 3341
`Sugiura, T., 3307
`Swartling, D. J., 3369
`
`Takada, H., 3307
`Takami, H., 3394, 3402
`Theobald, C. J., 3413
`Thimmaiah, K. N., 3358
`Thomson, R. J., 3349
`Todd, R. S., 3388
`True, R. A., 3319
`
`Ushio, Y., 3307
`
`Wakelin, L. P. G., 3349
`Webster, L. K., 3349
`Wiggall, K. J., 3413
`Wikel, J. H., 3423
`Williams, T. L., 3349
`
`Yamazaki, S., 3307
`Yokoyama, T., 3325
`Yue, S. Y., 3331
`
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`

`
`3426
`
`J. Med. Chem. 1992, 35, 3426-3428
`cmoa
`
`Specific Inhibition of HIV-1 Protease by
`Boronated Porphyrins
`
`The rapid spread of human immunodeficiency virus
`(HIV), the causative agent of acquired immunodeficiency
`syndrome (AIDS), throughout the world has prompted an
`intense search for antiretroviral therapeutics. An analysis
`of nonpeptide compounds with useful pharmacological
`properties led us to test the ability of porphyrins to inhibit
`HIV protease (HIV PR). Determination of the IC50’s of
`natural porphyrins on purified recombinant HIV-1 and
`HIV-2 PRs revealed that they are micromolar inhibitors
`of these enzymes. Availability of a series of carboxyl
`carborane ester derivatives of porphyrins synthesized as
`experimental neutron-capture therapeutics led to the
`discovery that compound 1, the tetrakiscarborane car-
`boxylate ester of 2,4-bis-(a,B-dihydroxyethyl)deutero-
`porphyrin IX” Table I), is a submicromolar inhibitor of
`HIV protease. This compound is also capable of inhibiting
`HIV-1 viral polyprotein processing in cultured mammalian
`cells (ex vivo).
`The in vitro effect of the porphyrin derivatives on HIV-1
`and HIV-2 PR activity was examined by monitoring the
`cleavage of a decapeptide substrate.3 The IC_-,0 values for
`a series of porphyrin-based compounds measured on HIV-1
`and HIV-2 PRs are shown in Table I. Since many of the
`derivatives were insoluble in buffer alone, 5% DMSO was
`used to increase solubility and to allow a comparison of
`the binding affinities of the various compounds. The best
`inhibitor is 1, with an IC50 of 185 nM for HIV-1 PR and
`700 nM for HIV-2 PR. The inhibitory potency of the
`porphyrin derivatives for HIV-2 PR is generally a factor
`of 2-5 less than for HIV-1 PR. Dipotassium salts of several
`of the inhibitors were soluble in aqueous solution and were
`assayed in the absence of DMSO. The IC50 values are
`shown in Table II.
`The photosensitivity of 1 made the metalloporphyrin
`derivatives (3, 5, and 6) preferable for subsequent kinetic
`analysis. These were easily prepared in high yield by
`standard techniques, as described in the supplementary
`material. Initial enzyme rates were fit to the Michaelis-
`Menten equation and kinetic constants were calculated
`using a nonlinear regression program.4 A Dixon plot for
`5 is shown in Figure 1. The appearance of the intersecting
`inhibition curves is consistent with a competitive mode of
`inhibition, with an inhibition constant (K,) of 140 :|: 25 nM.
`Compound 3 also appears to be a competitive inhibitor,
`with a K, of 85 :|: 5 nM (data not shown). The effect of
`salt concentration on inhibition by 3 was examined. The
`IC50 in 0.3 M NaCl (85 nM) was similar to the value ob-
`tained with 1 M NaCl (100 nM). This low ionic strength
`dependence of inhibition is important for in vivo appli-
`cations.
`The compounds assayed can be divided into three
`
`(1) Hill, J. S.; Kalil, S. B.; Kaye, A. H.; Stylli, S. S.; Koo, M.-S.;
`Gonzales, M. F.; Vardaxis, N. J.; Johnson, C. I. Selective tumor
`uptake of a boronated porphyrin in an animal model of cere-
`bral glioma. Proc. Natl. Sci. U.S.A. 1992,89, 1785-1789.
`(2) Kalil, S. B.; Koo, M.-S. Synthesis of Tetrakis—carborane-car-
`boxylate Esters of 2,4-Bis-(a,;3-dihydroxyethyl)-deutero-
`porphyrin IX.
`J. Chem. Soc., Chem. Commun. 1990, 24,
`1769-1771.
`(3) DesJarlais, R. L.; Seibel, G. L.; Kuntz, I. D.; Furth, P. S.;
`Alvarez, J. C.; Ortiz de Montellano, P. R.; DeCamp, D. L.;
`Babé, L. M.; Craik, C. S. Structure—based design of nonpeptide
`inhibitors specific for the human immunodeficiency virus 1
`protease. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 6644-6648.
`Leatherbarrow, R. J. Enzfitter. A Non-linear Regression Data
`Analysis Program for the IBM-PC. Elsevier Biosuft, Cam-
`bridge, U.K, 1987.
`
`mmmmslap.
`
`0002
`
`mm
`newnew lu-3 2»:
`us,
`
`39-3 43.3 53-:
`uIA~I
`
`
`
`1/v,(umol/min.mg)
`
`200
`
`'1?
`300
`
`400
`
`100
`"M
`
`[5]
`
`Figure 1. Dixon plot of 5 inhibition of HIV-1 PR. Purified HIV-1
`PR (6 X 10" mg/mL) was incubated with 5 in 50 mM sodium
`acetate buffer, pH 5.5, containing 1 mM dithiothreitol, 1 mM
`EDTA, and 1 M NaCl. After 1 min, the substrate peptide was
`added to give the final substrate concentrations shown. The assay
`solutions were incubated for 30-45 min at 37 °C and enzyme
`activity was determined by quantitation of the hydrolysis products
`on HPLC.
`
`(1) carborane esters, (2) noncarborane esters, and
`classes:
`(3) protoporphyrin IX. The best inhibitor in vitro is 1,
`which is esterified with four molecules of 1,2-dicarha-clo-
`so-dodecaboranecarboxylic acid. Although complexation
`with Co(II) or Cu(II) weakens binding about 10-fold, ad-
`dition of Mn(III) has only 2-fold effect on inhibition, in-
`dicating that the hexacoordinate Mn(III) may be able to
`make favorable ionic interactions with the enzyme. Re-
`moval of all four carborane moieties, as in 12, substantially
`reduces inhibition. Removal of only two cages, as in 2, has
`little effect on binding. This suggests that only two of the
`four closo-carborane cages are responsible for most of the
`binding interaction. The metacarborane isomer, 9, binds
`approximately 60-fold less tightly, indicating that not only
`the presence of the carborane groups but also their isom-
`eric conformation is important. Adding a methyl group
`to the unsubstituted carborane cage CH, as in 4, also
`substantially decreases the binding affinity. The carborane
`cages thus appear to have a specific interaction with HIV
`PR which results in high affinity between the molecule and
`enzyme. Replacement of the carborane cages with simi-
`larly sized but less hydrophobic groups such as benzoyl
`(10), adamantoyl (7), or even B-napthoyl (11) groups gives
`inhibitors with IC50 values in the low micromolar range,
`suggesting the importance of supplying hydrophobic
`groups at these positions. The effect of the porphyrin
`derivatives on HIV-2 PR generally follows the same trend,
`with most of the IC50 values being several-fold higher.
`The cytotoxicity of compounds (LD5o) and their ability
`to inhibit capsid protein processing ex vivo during 4—h
`incubations (IC5o) are shown in Table I. A plasmid which
`encodes the HIV-1 proviral genome, with the exception of
`the gp 160 envelope protein,5 was stably introduced into
`the monkey cell line COS 7. Cloned progeny, COS A6 cells,
`constitutively release viral capsids into the media.
`In-
`hibition of polyprotein processing was determined by
`measuring the amount of p24 present in the viral capsid
`samples with an ELISA assay. The decrease in the amount
`of detectable p24 antigen correlated with a specific in-
`hibition of HIV PR activity, as judged by the accumulation
`of capsid precursor in conjunction with a disappearance
`of the p24 mature protein band in Western blots (data not
`
`(5) Page, K. A.; Landau, N. R.; Littman, D. R. Construction and
`use of a human immunodeficiency virus vector for analysis of
`virus infectivity. J. Virol. 1990, 64, 5270-5276.
`
`0022—2623/ 92/ 1835-3426$03.00/ 0 © 1992 American Chemical Society
`
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`
`Communications to the Editor
`
`Journal of Medicinal Chemistry, 1992, Vol. 35, No. 18
`
`3427
`
`Table I.
`
`In Vitro and Cell Culture Potencies of Porphyrin Derivatives
`
`
`
`lC50, in vitro,“ [.l.M
` entry Rm R3 HIV-1 HIV-2 LD50,” pM IC50, ex vivo,‘ }IM
`
`
`
`
`
`1
`0COB..,H..C,
`H2
`0.185
`0.70
`25
`25
`2
`R1 = H
`H2
`0.275
`1.0
`75
`<50
`R2 = OCOBIUHHC,
`OCOBwHuC2
`3
`OCOB10H,4C;,
`4
`oCoB..,H..o2
`5
`OCOBIDHHCZ
`6
`OCO(adamantoy1)
`7
`OC0-P-[(CH3)2N]benzoyl
`8
`m-OCOBNHHCZ
`9
`OCOCGH5
`10
`OCO(B-naphthoyl)
`ll
`OH
`12
`Protoporphyrin IX
`U-75875“
`
`70
`25
`30
`150
`250
`>250
`250
`250
`250
`250
`<50
`45
`
`65
`10
`>70
`25
`ND”
`75
`>150
`>100
`>150
`>200
`>200
`0.75
`
`
`
`Mn(III)
`Hz
`Cu(II)
`C0(II)
`H2
`Hg
`H2
`H2
`H2
`H2
`
`0.40
`0.70
`0.975
`2.25
`5
`7
`12
`14
`14
`280
`300
`<0.001
`
`1.2
`1.55
`2.2
`1.5
`13
`18
`11
`30
`23
`480
`500
`0.03
`
`‘Cells were incubated
`“Determined in the presence of 5% DMSO. "Cytotoxicity toward COS A6 cells cultured in the absence of FCS.
`with inhibitor in 2.5 mL of Dulbecco’s phosphate-buffered saline. After 15 min, 2.5 mL of media containing 10% FCS as well as inhibitor
`was added. Cells were incubated for an additional 3.75 h, after which viral capsids were isolated from the culture supernatant. dNot
`determined.
`'-‘Reference 7.
`
`ICM, for Porphyrin Derivatives on HIV PR in the
`Table II.
`Absence of DMSO
`
`1050. #M
`HIV-1
`HIV-2
`0.05
`0.230
`0.10
`0.70
`
`compd
`l
`3
`
`compd
`4
`5
`
`IC50: LLM
`HIV-1
`HIV-2
`0.90
`0.550
`0.725
`0.470
`
`shown). The MTT stain assay was used to obtain LD50
`values for all the compounds tested.“ The peptidomimetic
`inhibitor U-75875 was used as a standard for HIV PR
`inhibition.7
`We have observed that the presence of albumin prevents
`the ability of the compounds to inhibit HIV-1 PR during
`short-term incubations (0.25—4 h); therefore ex vivo IC.L-,0
`values shown in Table I were determined in the presence
`of a reduced concentration of fetal calf serum (FCS).
`However, COS A6 cells require 10% FCS for optimal
`
`(6) Mosmann, T. Rapid colorimetric assay for cellular growth and
`survival: application to proliferation and cytotoxicity assays.
`J. Immunol. Methods 1983, 65, 55-63.
`(7) Ashorn, P.; McQuade, T. J.; Thaisrivongs, S.; Tomasselli, A.
`G.; Tarpley, W. G.; Moss, B. An inhibitor of the protease
`blocks maturation of human and simian immunodeficiency
`viruses and spread of infection. Proc. Natl. Acad. Sci. U.S.A.
`1990, 87, 7472-7476.
`
`[C50 for 1 on Viral and Cellular Aspartyl Proteases
`Table III.
`protease
`IC5,,, }LM
`protease
`IC5Q, ;.LM
`renin
`3
`HIV-1
`0.05
`cathepsin D
`10
`HIV-2
`0.23
`pepsin
`4
`SIV
`0.25
`
`growth and viability and certain porphyrin derivatives
`show cytotoxicity toward COS A6 cells at <1OO /.eM con-
`centrations when cultured in the absence of FCS (Table
`I, LD50). Cymtoxicity is reduced by culturing COS A6 cells
`in 10% FCS. Under those conditions, the LD50 for 1-12
`is >250 [LM (data not shown). Compound 1 has similar
`LD5O values in C6 glioma and V79 CHO cells (100-125 /.LM
`and 2150 )uM, respectively) in the presence of FCS, as
`measured by standard colony survival techniques (J. H.
`Hill and B. H. Laster, personal communication). Moreo-
`ver, 1 is tolerated in mice at doses as high as 200 mg/ kg,
`with no apparent signs of morbidity or mortality of ani-
`mals} Since mice receiving 1 at 100 mg/kg by iv bolus are
`exposed to peak plasma concentrations of approximately
`900 LLM, the ex vivo LD50 values determined here may not
`be representative of the in vivo tolerance of compound 1
`or its metallo derivatives. A more serious consideration
`is the potential usefulness in clinical therapy of drugs
`which are inactivated by albumin. The antagonistic effect
`of albumin in cell culture may not reflect the situation in
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`
`3428 Journal of Medicinal Chemistry, 1992, Vol. 35, No. 18
`
`whole animals, where serum proteins can bind porphyrins
`and deliver them to various tissues rather than seques-
`tering them.8
`To address selectivity, the effect of 1 on other aspartyl
`proteases was evaluated.
`IC50 values of the water-soluble
`dipotassium salt of 1 measured in the absence of DMSO
`are shown in Table III. Compound 1 is approximately
`5-fold more effective for HIV-1 PR than for the closely
`related HIV-2 and SIV PRs, and at least 60-fold more
`inhibitory for HIV-1 PR compared to cellular aspartyl
`proteases.
`We have found that boronated porphyrins are inhibitors
`of HIV-1 PR and HIV-2 PR. Compound 1 is a submi-
`cromolar inhibitor in vitro and inhibits polyprotein pro-
`cessing in cell culture at micromolar concentrations. It
`selectively inhibits I-HV PR over cellular aspartyl proteases.
`Kinetic studies on metalloporphyrin derivatives suggest
`that tetracarboranyl porphyrins are competitive inhibitors
`of HIV-1 PR. Compound 1 represents a new class of HIV
`
`(8) Muller-Eberhard, U.; Nikkjlii, H. Transport of Tetrapyrroles
`by Proteins. Semin. Hematol. 1989, 26, 86-104.
`
`Communications to the Editor
`
`PR inhibitors which are promising candidates for anti-
`AIDS therapeutics.
`
`Acknowledgment. We wish to thank Dr. Alfredo To-
`masselli of the Upjohn Company for his kind gift of the
`inhibitor U-7 5875. This work was supported in part by
`grant CA 37961 to S.B.K. from the NIH, NCI and grant
`GM 39552 to C.S.C. from NIH. D.L.D. is a recipient of
`NIH Fellowship GM 13369. R.S. is a Fulbright/MEC
`postdoctoral fellow.
`Supplementary Material Available: Experimental proce-
`dures for the synthesis of carborane derivatives and in vitro and
`ex vivo assays are provided (6 pages). Ordering information is
`given on any current masthead page.
`
`Dianne L. DeCamp, Lilia M. Babé, Rafael Salto
`Jeanne L. Lucich, Myoung-Seo Koo
`Stephen B. Kahl,* Charles S. Craik*
`Department of Pharmaceutical Chemistry
`School of Pharmacy
`University of California
`San Francisco, California 94143-0446.
`Received May 21, 1992
`
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