WO1997049668A1 - Inhibiteurs de cysteine protease - Google Patents

Inhibiteurs de cysteine protease Download PDF

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Publication number
WO1997049668A1
WO1997049668A1 PCT/US1997/011501 US9711501W WO9749668A1 WO 1997049668 A1 WO1997049668 A1 WO 1997049668A1 US 9711501 W US9711501 W US 9711501W WO 9749668 A1 WO9749668 A1 WO 9749668A1
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WO
WIPO (PCT)
Prior art keywords
amino
leucinyl
methyl
hexanone
benzyloxycarbonyl
Prior art date
Application number
PCT/US1997/011501
Other languages
English (en)
Inventor
Thomas Joseph Carr
Robert Wells Marquis, Jr.
Hye-Ja Oh
Yu Ru
Scott Kevin Thompson
Daniel Frank Veber
Dennis Shinji Yamashita
Jack Hwekwo Yen
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Smithkline Beecham Corporation
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Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO1997049668A1 publication Critical patent/WO1997049668A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6472—Cysteine endopeptidases (3.4.22)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes

Definitions

  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
  • the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
  • the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
  • An object of the present invention is to provide compounds which inhibit cysteine proteases, particularly cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.
  • this invention provides a compound according to Formula I.
  • this invention provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting cysteine protease, especially cathepsin K.
  • the compounds of this invention are useful for treating diseases characterized by bone loss, such as osteoporosis and periodontitis or by excessive cartilage or matrix degradation, such as osteoarthritis.
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • Prodrugs are any covalentiy bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases where the inventive compounds may exist in tautomeric forms, e.g., keto-enol tautomers, each tautomeric form is included within the scope of the present invention, whether existing in equilibrium or predominantly in one form.
  • any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
  • C]-6alkyl, or any subcombination thereof, e.g. Cj- 4 alkyl, as applied herein includes, but is not limited to, as appropriate for a particular subcombination, substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n- pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any Cj .
  • 6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R') 2 , C(0)N(R')2, carbamyl or C ⁇ _ 4 alkyl, where R' is Ci-6alkyl.
  • Alkoxy means a moiety having an ether oxygen substituted with C].
  • 0 alkyl e.g., in general, -O-Ci- ⁇ alkyl.
  • two adjacent C ⁇ . 4 alkoxy substituents may be combined to form a methylenedioxy ring system.
  • Phenoxy is -O-phenyl.
  • Ar or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to four moieties selected from the group consisting of: halogen; C j .
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ar refers to the aryl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical.
  • DMF refers to dimethyl formamide
  • DEA diethylamine
  • DIEA diisopropylethylamine
  • EDCI refers to N-ethyl- N'(dirnethylaminopropyl)-carbodiimide
  • HOBT 1-hydroxybenzotriazole
  • NMM is N-methylmorpholine
  • NMP is N-methyl pyrrolidinone
  • TFA trifluoroacetic acid
  • THF refers to tetrahydrofuran.
  • the alkoxy methyl ketone 5-Scheme 1 is prepared by formation of the bromide 3-Scheme 1 from 2-Scheme 1 with hydrogen bromide in acetic acid, displacement of the bromide with benzoyl formic acid and potassium fluoride in DMF, hydrolysis of the benzoyl formate with potassium bicarbonate in THF, and alkylation of the alcohol 4-Scheme 1 with an alkylating agent (such as ethyl iodide, methyl iodide or benzyl bromide) and silver (I) oxide in methylene chloride.
  • an alkylating agent such as ethyl iodide, methyl iodide or benzyl bromide
  • silver (I) oxide in methylene chloride.
  • Hydrogenolysis of the Cbz group with hydrogen gas over palladium on carbon in ethanol/6 N aqueous hydrochloric acid gives the amine 6-Scheme 1.
  • acyl chloride such as acetyl chloride or benzoyl chloride, or phenoxyacetyl chloride
  • a chloroformate such as 4-carbomethoxybenzyl chloroformate, (R)-l-phenylethyl chloroformate, (S)-l-phenylethyl chloroformate, cyclohexylmethyl chloroformate, 2- methoxybenzyl chloroformate, 4-chlorobenzyl chloroformate, 3,4-dimethylbenzyl chloroformate, cyclopentylmethyl chloroformate, 1-naphthylmethyl chloroformate or 4- fluorobenzyl chloroformate), a carbamoyl chloride (such as 1,2,3,4-tetrahydroisoquinolyl chloride, as 1,2,3,4-tetrahydroquinolyl chloride or N-benzyl-N-methylcarbamoyl chloride) or
  • Bromide 1 -Scheme 4 is treated with a mercaptan (such as 2-phenylethyl mercaptan, n-propyl mercaptan, n-butyl mercaptan, thiophenol or benzyl mercaptan) or an acidic alcohol (such as 1,1,1,3,3,3- hexafluoro-2-propanol, phenol or 3,4-methylenedioxyphenol) and potassium fluoride in DMF to provide 2-Scheme 4.
  • a mercaptan such as 2-phenylethyl mercaptan, n-propyl mercaptan, n-butyl mercaptan, thiophenol or benzyl mercaptan
  • an acidic alcohol such as 1,1,1,3,3,3- hexafluoro-2-propanol, phenol or 3,4-methylenedioxyphenol
  • This material is treated with hydrogen and 10% palladim on carbon in methanol to provide 4-Scheme 6 which is converted to amide 5-Scheme 6 by treatment with a carboxylic acid (such as N-Cbz-L-leucine, or N-Cbz-L-leucinyl-L-leucine), a peptide coupling reagent (such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide or 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), 1-hydroxybenzotriazole and diisopropylethylamine in DMF. Alcohol 5-Scheme 6 is then treated with Jones reagent in acetone to provide 6-Scheme 6.
  • a carboxylic acid such as N-Cbz-L-leucine, or N-Cbz-L-leucinyl-L-leucine
  • amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
  • compositions of the compounds of Formula I may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the compounds of Formula I are useful for treating diseases wherein the underlying pathology is responsive to inhibition of cysteine protease activity, especially cathepsin K activity.
  • the compounds of Formula I are useful for the treatment of conditions where undesirable bone resorption is a factor, such as osteoporosis, periodontitis, Paget's disease, hypercalcemia of malignancy, or metabolic bone disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
  • This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of Formula I, alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • a compound of Formula I alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone may be used to prevent bone loss or to increase bone mass.
  • parenteral administration of a compound of Formula I is preferred.
  • the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K.
  • the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect. Determination of cathepsin K proteolytic catalytic activity
  • v is the velocity of the reaction with maximal velocity V m
  • A is the concentration of substrate with Michaelis constant of K a
  • / is the concentration of inhibitor
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-k 0 b s t)] /k oos
  • the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.
  • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium. The beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded.
  • the osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample.
  • the cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl0 4 /mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium).
  • a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL).
  • the tubes were incubate at 37°C for 30 min.
  • 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h.
  • Each treatment was screened in quadruplicate.
  • the slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h.
  • the slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C.
  • the slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
  • the TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21 W confocal microscope.
  • Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-d D is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane.
  • N-methyl morpholine (1.07 g, 10.6 mmol, 1.16 mL) and isobutyl chloroformate (1.45 g, 10.6 mmol, 1.38 mL) are added.
  • the mixture is stirred at -40°C for 15 minutes and then filtered into a cold flask to remove precipitated salts.
  • To the filtered solution is added an excess of the previously prepared diazomethane solution and the mixture is allowed to stand at 0°C for 16 h.
  • An excess of 30% HBr in acetic acid is added at 0°C and the solution is then washed successively with 1.0N citric acid, saturated aqueous sodium bicarbonate (carefully), and brine.
  • Example 4(a) The compound of Example 4(a) ( 1.02 g, 1.9 mmol) was stirred vigorously in a mixture of tetrahydrofuran (100 mL) and 1.0M potassium bicarbonate (100 mL) at room temperature for 18 hours. The layers were seperated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and evaporated to give the title compound as a white solid (0.768 g).
  • Example 5 The compound of Example 5 (250 mg, 0.60 mmol) was dissolved in EtOH (40 ml) and 6 N aqueous hydrochloric acid (0.6 ml) then 10% palladium on carbon (60 mg) was added and the reaction was stirred under a balloon of hydrogen gas for 3h. The reaction mixture was filtered and the filtrate was diluted with toluene (2 x 100 ml) and was concentrated in vacuo to remove residual water to produce a white foam which was used in the next reaction without further purification.

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Abstract

Composés qui inhibent la cathepsine K et sont utiles pour traiter des maladies se traduisant par une perte cartilagineuse ou osseuse excessive.
PCT/US1997/011501 1996-06-13 1997-06-13 Inhibiteurs de cysteine protease WO1997049668A1 (fr)

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US2047896P 1996-06-13 1996-06-13
US60/020,478 1996-06-13

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034117A1 (fr) * 1997-01-30 1998-08-06 The University Of Liverpool Cathepsine k et cancer du sein
US5998470A (en) * 1995-10-30 1999-12-07 Smithkline Beecham Corporation Protease inhibitors
US6514997B2 (en) 1999-12-03 2003-02-04 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US6534530B1 (en) 1999-08-04 2003-03-18 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
US6562842B2 (en) 1995-10-30 2003-05-13 Smithkline Beecham Corporation Protease inhibitors
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
US6610730B2 (en) 2000-04-14 2003-08-26 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US6632825B2 (en) 2000-06-14 2003-10-14 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US6995142B2 (en) 1998-04-30 2006-02-07 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525420A1 (fr) * 1991-07-01 1993-02-03 Mitsubishi Chemical Corporation Pseudopeptides et peptides caractérisés par une partie méthyle cétone substituée à la terminaison C comme inhibiteurs de thiol protéase
EP0603873A1 (fr) * 1992-12-25 1994-06-29 Mitsubishi Chemical Corporation Dérivés d'aminocétone
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525420A1 (fr) * 1991-07-01 1993-02-03 Mitsubishi Chemical Corporation Pseudopeptides et peptides caractérisés par une partie méthyle cétone substituée à la terminaison C comme inhibiteurs de thiol protéase
EP0603873A1 (fr) * 1992-12-25 1994-06-29 Mitsubishi Chemical Corporation Dérivés d'aminocétone
EP0611756A2 (fr) * 1993-02-19 1994-08-24 Takeda Chemical Industries, Ltd. Alcool et aldéhyde dérivés comme inhibiteur de cathepsin L et comme inhibiteur de la résorption osseuse

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6586466B2 (en) 1995-10-30 2003-07-01 Smithkline Beecham Corporation Carbohydrazide-protease inhibitors
US5998470A (en) * 1995-10-30 1999-12-07 Smithkline Beecham Corporation Protease inhibitors
US6057362A (en) * 1995-10-30 2000-05-02 Smithkline Beecham Corporation Protease inhibitors
US6232342B1 (en) 1995-10-30 2001-05-15 Smithkline Beecham Corporation Protease inhibitors
US6284777B1 (en) 1995-10-30 2001-09-04 Smithkline Beecham Corporation Carbohydrazide protease inhibitors
US6331542B1 (en) 1995-10-30 2001-12-18 Smithkline Beecham Corporation Protease inhibitors
US6562842B2 (en) 1995-10-30 2003-05-13 Smithkline Beecham Corporation Protease inhibitors
WO1998034117A1 (fr) * 1997-01-30 1998-08-06 The University Of Liverpool Cathepsine k et cancer du sein
US6995142B2 (en) 1998-04-30 2006-02-07 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US6534530B1 (en) 1999-08-04 2003-03-18 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
US6514997B2 (en) 1999-12-03 2003-02-04 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7563784B2 (en) 2000-03-21 2009-07-21 Smithkline Beecham Corporation Protease inhibitors
US6610730B2 (en) 2000-04-14 2003-08-26 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US6872745B2 (en) 2000-04-14 2005-03-29 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US6632825B2 (en) 2000-06-14 2003-10-14 Agouron Pharmaceuticals, Inc. Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors

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