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US20070123539A1 - Treatment of Restenosis and Stenosis with Dasatinib - Google Patents

Treatment of Restenosis and Stenosis with Dasatinib Download PDF

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Publication number
US20070123539A1
US20070123539A1 US11/551,116 US55111606A US2007123539A1 US 20070123539 A1 US20070123539 A1 US 20070123539A1 US 55111606 A US55111606 A US 55111606A US 2007123539 A1 US2007123539 A1 US 2007123539A1
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Prior art keywords
dasatinib
agents
bms
patient
additional therapeutic
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US11/551,116
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Jie Wu
Zhengming Chen
Kapil Bhalla
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H Lee Moffitt Cancer Center and Research Institute Inc
University of South Florida St Petersburg
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H Lee Moffitt Cancer Center and Research Institute Inc
University of South Florida St Petersburg
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Priority to US11/551,116 priority Critical patent/US20070123539A1/en
Assigned to H. LEE MOFFITT CANCER CENTER reassignment H. LEE MOFFITT CANCER CENTER ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, ZHENGMING
Assigned to UNIVERSITY OF SOUTH FLORIDA reassignment UNIVERSITY OF SOUTH FLORIDA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BHALLA, KAPIL, WU, JIE
Publication of US20070123539A1 publication Critical patent/US20070123539A1/en
Priority to US13/273,731 priority patent/US8815260B1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • This invention relates to prevention and treatment of artery obstructive diseases. More specifically, this invention relates to methods for treating or preventing restenosis and stenosis in humans using dasatinib.
  • Balloon angioplasty and stenting are widely used procedures for coronary artery disease.
  • renarrowing (restenosis) of the dilated artery occurs in 25-40% of patients within six months after these procedures, which requires repeat angioplasty or bypass surgery (Dangas and Kuepper, 2002; Michaels and Chatterjee, 2002). Therefore, restenosis represents a major problem limiting the long-term efficacy of these revascularization therapies.
  • narrowing (stenosis) of the transplanted artery can also occur that necessitates further medical treatments.
  • vascular injury and proliferation of VSMCs are critical events in the pathogenesis of artery obstructive diseases such as restenosis (Bailey, 2002; Levitzki, 2005; Sanz-Gonzalez et al., 2004). While several growth factors and cytokines are involved in the development of restenosis, many lines of evidence have indicated that PDGF plays a prominent role in the pathogenesis of restenosis. PDGF is the most potent mitogen and motogen for VSMCs (Heldin and Westermark, 1999). PDGF is present at sites of vascular injury from activated platelets, monocytes, and cells of the artery wall (Raines, 2004).
  • exogenous PDGF in animal arteries can induce intimal thickening through stimulation of VSMC proliferation and migration and synthesis of extracellular matrix (Pompili et al., 1995).
  • inhibition of PDGF as well as PDGFR can suppress development of restenotic lesions in animal models (Ferns et al., 1991; Levitzki, 2005; Myllarniemi et al., 1999; Sirois et al., 1997).
  • Imatinib (Gleevec, ST1571, CGP57148B) is the first protein tyrosine kinase inhibitor that has been successfully developed into a targeted therapy drug. It is currently used to treat chronic myeloid leukemia (CML) and gastrointestinal stromal tumor based on inhibition of Bcr-Abl and c-Kit protein tyrosine kinases, respectively (Deininger et al., 2005; Logrono et al., 2004). Besides Bcr-Abl and c-Kit, imatinib also inhibits PDGFR tyrosine kinase (Buchdunger et al., 1996; Druker et al., 1996).
  • imatinib inhibits restenosis after balloon angioplasty and stenosis after allograft (Myllarniemi et al., 1999; Sihvola et al., 2003). Inhibition of PDGFR by imatinib, however, requires micromolar concentrations in cell-based assays (Buchdunger et al., 1996; Sanz-Gonzalez et al., 2004).
  • a stent is a wire mesh tube used to prop open an artery after angioplasty. Restenosis is found to be less common in stented arteries.
  • the present invention provides a novel method for treating or inhibiting artery obstructive disease, such as restenosis (typically encountered after angioplasty and stenting procedures) and stenosis (typically encountered after coronary artery bypass surgery), in a subject by administering to the subject a therapeutically effective amount of dasatinib or a derivative thereof
  • the present invention provides a method of treating or inhibiting restenosis or stenosis in a patient comprising administering to a patient in need of such treatment a composition comprising dasatinib or a pharmaceutically acceptable derivative thereof in an amount effective to treat or inhibit restenosis or stenosis.
  • the dasatinib is administered orally.
  • the dasatinib is administered with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents can include antiplatelet agents, antimigratory agents, antifibrotic agents, antiproliferatives, antiinflammatories and combinations thereof
  • the one or more additional therapeutic agents is sirolimus or paclitaxel.
  • the present invention provides a method of treating or inhibiting artery obstructive disease in a patient comprising administering to a patient in need of such treatment a composition comprising dasatinib or a pharmaceutically acceptable derivative or analog thereof in an amount effective to treat artery obstructive disease.
  • the present invention provides a method of treating or inhibiting restenosis or stenosis in a patient comprising administering to a patient in need of such treatment a composition comprising a dual Src/PDGFR inhibitor.
  • the present invention provides a method of treating or inhibiting artery obstructive disease in a patient comprising administering to a patient in need of such treatment a composition comprising a dual Src/PDGFR inhibitor.
  • the dual Src/PDGFR inhibitor is administered with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents can include antiplatelet agents, antimigratory agents, antifibrotic agents, antiproliferatives, antiinflammatories and combinations thereof
  • the present invention provides a method of treating restenosis in a patient comprising administering to a patient in need of such treatment a composition comprising a nanomolar concentration of a PDGFR tyrosine kinase inhibitor.
  • the present invention provides a stent having a coating comprising dasatinib or a pharmaceutically acceptable derivative thereof
  • the stent at least one additional therapeutic agent coated thereon.
  • the additional therapeutic agent can be selected from the group consisting of antiplatelet agents, antimigratory agents, antifibrotic agents, antiproliferatives, antiinflammatories and combinations thereof
  • the additional therapeutic agent is sirolimus or paclitaxel.
  • the present invention provides a medical device comprising an implantable device having a coating comprising a therapeutic amount of dasatinib or a pharmaceutically acceptable derivative thereof for the site-specific, controlled release of the therapeutic amount.
  • the device can include at least one additional therapeutic agent coated thereon.
  • the additional therapeutic agent can include antiplatelet agents, antimigratory agents, antifibrotic agents, antiproliferatives, antiinflammatories and combinations thereof
  • FIG. 1 shows the effect of BMS-354825 (Dasatinib, SPRYCEL) on PDGF-stimulated activation of PDGFR, STAT3, Akt, and Erk in rat A10 VSMCs.
  • A Time-dependent activation of PDGFR, STAT3, Akt, and Erk2 in A10 cells.
  • Subconfluent A10 cells were serum starved for 18 h, pre-incubated with BMS-354825 (50 nM, 20 min) or DMSO ( ⁇ ) for 20 min, and then treated with PDGF-BB (5 ng/ml) for the indicated time.
  • C BMS-354825 inhibited PDGFR tyrosine kinase activity in vitro.
  • PDGFR was immunoprecipitated from A10 cells stimulated with PDGF-BB (5 ng/ml, 5 min). A portion of each immunoprecipitate (5/7) was used for in vitro kinase assay in the presence of BMS-354825 at the indicated concentrations. The remaining immunoprecipitates were used for immunoblotting analysis with anti-PDGFR ⁇ antibody (inset).
  • the graph is derived from three experiments.
  • FIG. 2 shows a comparison of the inhibitory effects of BMS-354825 and imatinib in A10 cells.
  • A10 cells were serum-starved, pre-incubated with indicated concentrations of BMS-354825 or imatinib for 20 min, and then stimulated with PDGF-BB (5 ng/ml, 5 min). Cell lysate supernatants were analyzed by immunoblotting similar to that described in FIG. 1A legend.
  • B Quantification of PDGFR pTyr signal intensities. Data were from two experiments.
  • FIG. 3 shows the inhibitory effects of BMS-354825 in primary culture of human AoSMCs.
  • Human AoSMCs were deprived from serum for 18 h, pre-incubated with indicated concentrations of BMS-354825 for 20 min and then stimulated with PDGF-BB (5 ng/ml, 5 min).
  • Cell lysate supernatants were analyzed for activation of PDGFR, STAT3, Akt, and Erk2 by immunoblotting.
  • FIG. 4 shows the inhibition of Src tyrosine kinase by BMS-354825.
  • c-Src was immunoprecipitated from serum-starved A10 cells (0) or A10 cells stimulated with PDGF (5 ng/ml) for the indicated time in the presence of absence of 50 nM BMS-354825.
  • Src kinase activity was determined by autophosphorylation and phosphorylation of GST-Gabl CT in the immune complex kinase assay (Ren et al., 2004). After autoradiography, the filter was used for immunoblotting analysis with an anti-Src antibody (lower panel).
  • FIG. 5 shows IGF-1R and EGFR are insensitive to BMS-354825.
  • A10 cells were serum-starved, pretreated with indicated concentrations of BMS-354825 (20 min) and then stimulated with IGF-1 (10 ng/ml, 10 min) or EGF (10 ng/ml, 10 min).
  • IGF-1R or EGFR was immunoprecipitated from cell lysate supernatants and analyzed by antibodies to pTyr and IGF-1R (A) or pTyr and EGFR (B).
  • FIG. 6 shows the effect of BMS-354825 on PDGF-stimulated cell migration.
  • Transwell cell migration assay was performed using PDGF-BB (5 ng/ml) as the chemoattractant in the presence or absence of BMS-354825 as indicated.
  • A For A10 cells, 1 ⁇ 10 4 cells were loaded into the upper chamber of each well. Each field was 0.8 ⁇ 0.6 mm. The data were from 2 (lanes 2, 3, 4) to 4 experiments performed in duplicate.
  • C For human AoSMCs, 0.5 ⁇ 10 4 cells per well were used. The results were from two experiments performed in duplicate.
  • FIG. 7 shows the inhibition of PDGF-stimulated cell proliferation and cell cycle progression by BMS-354825.
  • A and
  • B A10 cells (2 ⁇ 10 4 cells/well) or human AoSMCs (3.5 ⁇ 10 4 cells/well) were cultured in DMEM/1% FBS plus indicated PDGF-BB and BMS-354825 for 6 days and viable cell number were determined. Data represent two triplicate experiments.
  • C A10 cells were incubated with or without PDGF-BB (10 ng/ml) and indicated concentrations of BMS-354825 for 16 h and processed for propidium iodide staining and flow cytometric analysis. The data represent two experiments performed in duplicate.
  • A10 cells (2 ⁇ 10 4 cells/well) were cultured in DMEM/1% FBS plus PDGF-BB in the presence of indicated concentrations of BMS-354825 for 6 days. After which, cells were washed and cultured in DMEM/1% FBS plus PDGF-BB with or without BMS-354825 for another 6 days. Viable cell number was determined on Day 12. The data were from three experiments performed in duplicate.
  • vascular smooth muscle cells are key events in the pathogenesis of restenosis that undermine the long-term benefit of widely performed balloon angioplasty and stenting procedures.
  • Platelet-derived growth factor (PDGF) is a potent mitogen and motogen for VSMCs and is known to play a prominent role in the intimal accumulation of smooth muscle cells.
  • BMS-354825 a novel protein tyrosine kinase inhibitor, BMS-354825 (dasatinib), on PDGF-stimulated VSMCs.
  • BMS-354825 is an orally bioavailable dual Src/Bcr-Abl tyrosine kinase inhibitor currently undergoing clinical trials in cancer patients.
  • BMS-354825 inhibited PDGF-stimulated activation of PDGF receptor (PDGFR), STAT3, Akt, and Erk2 in rat A10 VSMCs and in primary cultures of human aortic smooth muscle cells (AoSMCs) at low nanomolar concentrations.
  • the 50% inhibition of the PDGFR ⁇ tyrosine kinase activity in vitro by BMS-354825 was observed at 4 nM.
  • BMS-354825 and another PDGFR inhibitor, imatinib (Gleevec, STI571) indicated that BMS-354825 is 67-fold more potent than imatinib in inhibition of PDGFR activation.
  • BMS-354825 also inhibited Src tyrosine kinase in A10 cells.
  • PDGF stimulated migration and proliferation of A10 cells and human AoSMCs, both of which were inhibited by BMS-354825 in a concentration dependent manner in the low nanomolar range.
  • Dasatinib (BMS-354825, SPRYCEL) has been approved by the U.S. FDA (Jun. 28, 2006) for (1) treatment of adults with all phases of chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy, including Gleevec (imatinib mesylate) and (2) treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy.
  • CML chronic myeloid leukemia
  • Pr+ALL Philadelphia chromosome-positive acute lymphoblastic leukemia
  • BMS-354825 is a potential novel therapeutic agent for cardiovascular diseases involving abnormal VSMC activities such as restenosis and stenosis.
  • Dasatinib is the generic name for the compound N-(2-chloro-6-methylphenyl)-2-[[6-[4[(2-hydroxyethyl)-1-pipperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate, also known as BMS-354825 and SPRYCEL, of the following formula I:
  • the compounds of Formula I may be prepared by the procedures described in PCT publication, WO 00/62778 published Oct. 26, 2000.
  • the compound of formula I may be administered as described therein or as described in WO2004/085388, or as further described below with respect to the treatment of restenosis/artery obstructive diseases.
  • Amounts of dasatinib (BMS-354825) effective to treat restenosis would broadly range between about 10 mg. and about 150 mg. per day, more generally range between about 35 mg. and about 140 mg. per day, and preferably between about 70 mg. and about 140 mg. per day (administered orally twice a day).
  • the rationale for the preferred dose range is based upon BMS-354825 dosing for CML and the clinical pharmacology data presented in “Dasatinib (BMS-354825) Oncologic Drug Advisory Committee (ODAC) briefing document, NDA-21-986, in which the Cmax was between approximately 60-120 nM.
  • BMS-354825 dasatinib
  • the arteries should be effectively targeted with lower doses because of relatively high concentrations of drug in the bloodstream following its oral administration and absorption in the intestine.
  • BMS-354825 doses should minimize the risk of toxicity.
  • BMS-354825 may be administered either alone or in conjunction with therapies aimed at blocking vascular smooth muscle cell proliferation and inflammation such as sirolimus-eluting stent and a paclitaxel-eluting stent.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of artery obstructive diseases, particularly restenosis, comprising the administration of a therapeutically effective amount of the compound of the present invention, either alone or in combination with other compounds useful in the treatment of artery obstructive diseases, with or without pharmaceutically acceptable carriers or diluents.
  • the compositions of the present invention may further comprise one or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like.
  • the compositions of the present invention may be administered orally or parenterally including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • compositions of the present invention may be delivered as a coating, or otherwise integral to, an implantable medical device such as stents.
  • Coated implantable devices may be prepared as described in U.S. Pat. No. 6,585,764 to Wright et al. and US2005/0214343A1 to Tremble et al.
  • the coated stent may further comprise one or more
  • compositions of this invention may be administered, for example, in the form of tablets or capsules, powders, dispersible granules, or cachets, or as aqueous solutions or suspensions.
  • carriers which are commonly used include lactose, corn starch, magnesium carbonate, talc, and sugar, and lubricating agents such as magnesium stearate are commonly added.
  • useful carriers include lactose, corn starch, magnesium carbonate, talc, and sugar.
  • emulsifying and/or suspending agents are commonly added.
  • sweetening and/or flavoring agents may be added to the oral compositions.
  • sterile solutions of the active ingredient(s) are usually employed, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of the solute(s) should be controlled in order to render the preparation isotonic.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously in the wax, for example by stirring. The molten homogeneous mixture is then poured into conveniently sized molds and allowed to cool and thereby solidify.
  • Liquid preparations include solutions, suspensions and emulsions. Such preparations are exemplified by water or water/propylene glycol solutions for parenteral injection. Liquid preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid preparations which are intended for conversion, shortly before use, to liquid preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • composition described herein may also be delivered transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the combinations of the present invention may also be used in conjunction with other well known therapies that are selected for their particular usefulness against the condition that is being treated.
  • the effective amount of the compounds of the combination of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.1 to 2 mg/kg of body weight of active compound per day, preferably at a dose from 0.1 to 2 mg/kg of body weight which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 2 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • Subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to protein tyrosine kinase-associated disorders.
  • the compounds of the combination of the present invention are preferably administered using the formulations of the invention.
  • compounds of the combination of the present invention can be administered orally, intravenously, or both or as drug-eluting stents.
  • the methods of the invention encompass dosing protocols such as once a day for 2 to 10 days, every 3 to 9 days, every 4 to 8 days and every 5 days. In one embodiment there is a period of 3 days to 5 weeks, 4 days to 4 weeks, 5 days to 3 weeks, and 1 week to 2 weeks, in between cycles where there is no treatment.
  • the compounds of the combination of the present invention can be administered orally, intravenously, or both, once a day for 3 days, with a period of 1 week to 3 weeks in between cycles where there is no treatment.
  • the compounds of the combination of the present invention can be administered orally, intravenously, or both, once a day for 5 days, with a period of 1 week to 3 weeks in between cycles where there is no treatment.
  • the treatment cycle for administration of the compounds of the combination of the present invention is once daily for 5 consecutive days and the period between treatment cycles is from 2 to 10 days, or one week.
  • a combination of the compound of the present invention is administered once daily for 5 consecutive days, followed by 2 days when there is no treatment.
  • the compounds of the combination of the present invention can also be administered orally, intravenously, or both, once every 1 to 10 weeks, every 2 to 8 weeks, every 3 to 6 weeks, and every 3 weeks.
  • the compound of formula I may be administered in a dose of 15-200 mg twice a day, or 30-100 mg twice a day. In one embodiment, the compound of formula I may be administered at 70 mg twice a day. In another embodiment, the compound of formula I may be administered in a dose of 50-300 mg once a day, or 100- 200 mg once a day.
  • the compound of formula I may be administered in a dose of 70-150 mg twice a day or 140-250 mg once a day.
  • the compound of formula I may be administered at 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130 or 140 mg twice a day, or doses in between.
  • the compound of formula I may be administered at 20, 30, 40, 50, 60, 70, 80, 100, 120, 140, 160, 180, 200, 220 or 240 mg once a day, or doses in between.
  • the compound of formula I may be administered either continuously or on an alternating schedule, such as 5 days on, 2 days off, or some other schedule as described above.
  • combinations of the instant invention may also be co- administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
  • the therapeutic agent(s) can be administered according to therapeutic protocols well known in the art.
  • the administration of the therapeutic agent(s) can be varied depending on the disease being treated and the known effects of the therapeutic agent(s).
  • the therapeutic protocols e.g., dosage amounts and times of administration
  • the therapeutic protocols can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
  • the invention also relates to a kit, wherein the agents/compounds are disposed in separate containers.
  • the invention also relates to a kit according to any of the foregoing, further comprising integrally thereto or as one or more separate documents, information pertaining to the contents or the kit and the use of the agents/inhibitors.
  • the invention also relates to a kit according to any of the foregoing, wherein the compositions are formulated for reconstitution in a diluent.
  • the invention also relates to a kit according to any of the foregoing, further comprising a container of sterile diluent.
  • the invention also relates to a kit according to any of the foregoing, wherein said compositions are disposed in vials under partial vacuum sealed by a septum and suitable for reconstitution to form a formulation effective for parental administration.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system, i.e., the degree of precision required for a particular purpose, such as a pharmaceutical formulation.
  • “about” can mean within 1 or more than 1 standard deviations, per the practice in the art.
  • “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.
  • the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • the term “about” meaning within an acceptable error range for the particular value should be assumed.
  • Restenosis is the renarrowing of an artery or other blood vessel following treatment, such as angioplasty, stent or bypass surgery, for coronary artery disease. Restenosis may also occur in valves after balloon valvuloplasty. Restenosis is less common in stented arteries.
  • Stepnosis is the narrowing or constriction of an opening, such as a blood vessel or heart valve. Fat, cholesterol and other substances that accumulate over time may clog the artery.
  • One way to widen a coronary artery is by using balloon angioplasty. Restenosis (renarrowing) of the widened segment occurs in some patients who undergo balloon angioplasty within about six months of the procedure. Restenosed arteries may have to undergo another angioplasty.
  • One way to help prevent restenosis is by using stents. Restenosis is less common in stented arteries. Stenosis can also occur after a coronary artery bypass graft operation. This procedure is done to reroute, or “bypass,” blood around clogged arteries. It also improves the supply of blood and oxygen to the heart. In this case, the stenosis may occur in the transplanted blood vessel segments. Like other stenosed arteries, they may need angioplasty or atherectomy to reopen them.
  • “Therapeutically effective amount” refers to an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to treat the diseases described herein.
  • treating or “treatment” and the like should be taken broadly. They should not be taken to imply that an animal is treated to total recovery. Accordingly, these terms include amelioration of the symptoms or severity of a particular condition or preventing or otherwise reducing the risk of further development of a particular condition.
  • methods of the invention may be applicable to various species of subjects, preferably mammals, more preferably humans.
  • the compounds of the present invention include the pharmaceutically acceptable derivatives thereof
  • a “pharmaceutically-acceptable derivative” denotes any salt, ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly), such as a prodrug, a compound of this invention, or a metabolite or residue thereof
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,
  • Suitable pharmaceutically-acceptable base addition salts include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of the invention. When a basic group and an acid group are present in the same molecule, a compound of the invention may also form internal salts.
  • prodrug refers to compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided by T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery systems,” Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., “Bioreversible Carriers in Drug Design,” American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • coated with reference to a stent or other implantable medical device is meant to be interpreted broadly to include compounds on the surface or otherwise integral to the device such that the therapeutic compound elutes from the device upon implantation in the subject.
  • BMS-354825 Inhibits PDGF-activated Signaling Pathways in VSMCs.
  • FIG. 1A also shows that STAT3, Akt, and Erk2 were activated by PDGF in A10 cells as measured by activation-specific phosphorylation and these were inhibited by BMS-354825.
  • PDGFR ⁇ was immunoprecipitated from A10 cells with or without prior PDGF stimulation (5 ng/ml, 5 min).
  • the PDGFR tyrosine kinase activity was determined in vitro in the immune complexes by autophosphorylation in the presence of various concentrations of BMS-354825.
  • FIG. 1C BMS-354825 inhibited PDGFR tyrosine kinase activity in a concentration-dependent manner.
  • the 50% inhibition of PDGFR ⁇ phosphorylation was observed at 4 nM BMS-354825.
  • imatinib In addition to inhibiting Bcr-Abl and c-Kit, imatinib also inhibits PDGFR tyrosine kinase.
  • A10 cells were pre-incubated with various concentrations of BMS-354825 or imatinib, stimulated with PDGF-BB, and activation of PDGFR, STAT3, Akt, and Erk2 were analyzed.
  • FIG. 2A shows that PDGF-stimulated PDGFR ⁇ tyrosine phosphorylation was completely blocked by 50 nM BMS-354825.
  • c-Src was immunoprecipitated from serum-starved A10 cells treated with PDGF-BB (5 ng/ml) for 0-30 min in the presence or absence of 50 nM BMS-354825, and the Src tyrosine activity was determined by an immune complex kinase assay using a GST fusion protein of Gabl fragment as an exogenous substrate (Ren et al., 2004).
  • c-Src isolated from A10 cells without exposure to BMS-354825 and PDGF had detectable kinase activity ( FIG. 4A ).
  • FIG. 2B shows that BMS-354825 potently inhibited c-Src tyrosine kinase in A10 cells.
  • the IC 50 for inhibition of c-Src autophosphorylation was 2.25 nM while the IC 50 for inhibition the exogenous substrate (GST-GablCT) was 2.0 nM.
  • IGF-1R and EGFR in A10 cells are not sensitive to BMS-354825 inhibition.
  • A10 cells also express IGF-1R and EGFR.
  • BMS-354825 inhibits other receptor tyrosine kinases in VSMCs.
  • IGF-1 induced IGF-1R tyrosine phosphorylation
  • EGF induced EGFR tyrosine phosphorylation in A10 cells.
  • No detectable inhibition of IGF-1R and EGFR tyrosine phosphorylation was observed when A10 cells were treated with up to 50 nM BMS-354825.
  • BMS-354825 Inhibits PDGF-stimulated VSMC Migration.
  • PDGF is a potent migratory stimulus for VSMCs.
  • Transwell cell migration assay was performed to determine the effect of BMS-354825 on PDGF-induced VSMCs migration.
  • A10 cells had a low basal migration activity.
  • PDGF (5 ng/ml) stimulated A10 cell migration 7-fold in our assay. This response was inhibited by BMS-354825 in a concentration-dependent manner (FIGS. 6 A-B). Consistent with the biochemical data, complete inhibition of PDGF-stimulated A10 cells migration was observed at 50 nM BMS-354825.
  • the primary human AoSMCs had a higher basal migration activity, which is 4 times that of A10 cells.
  • PDGF 5 ng/ml
  • migration of human AoSMCs was increased 3-fold.
  • PDGF-stimulated human AoSMC cell migration was inhibited by BMS-354825 ( FIG. 6C ).
  • rat A10 cells were incubated in medium containing low serum (1% FBS), PDGF (10 ng/ml), and/or 0-50 nM BMS-354825 for 6 days and viable cell numbers were determined.
  • FBS low serum
  • PDGF 10 ng/ml
  • BMS-354825 effectively inhibited PDGF-stimulated A10 cell proliferation.
  • Complete inhibition was achieved at 50 nM of BMS-354825.
  • Similar results were obtained in human AoSMCs ( FIG. 7B ).
  • FIG. 6C shows that PDGF decreased the percentage of cells in G1 phase from 88.65% to 65.44%, while it increased the percentages of cells in S and G2 phases from 10.4% and 0.99% to 23.83% and 10.74%, respectively.
  • the effect of PDGF was suppressed by BMS-354825, such that in the percentages of cells in G1, S, and G2 phases were 88.29%, 7.99% and 3.75% in cells treated with PDGF in the presence of 50 nM BMS-354825 ( FIG. 7C ).
  • Antibodies to phosphotyrosine, phospho-Akt, and phospho-Stat3 were from Cell Signaling (Beverly, Mass.).
  • Anti-PDGFR ⁇ (catalog number: 06-498, for immunoblotting) was from Upstate Biotechnology (Lake Placid, N.Y.).
  • Antibodies to PDGFR ⁇ (catalog number PC-17, for immunoprecipitation) and Src (catalog number OP07, for immune complex kinase assay) were from Calbiochem (San Diego, Calif.).
  • Antibodies to Akt, STAT3, Erk1/2, Src for immunoblotting
  • insulin-like growth factor-1 receptor (IGF-1R) insulin-like growth factor-1 receptor
  • EGFR epidermal growth factor receptor
  • the anti-activated Erk1/2 antibody was from Promega (Madison, Wis.).
  • PDGF-BB was from PeproTech (Rocky Hill, N.J.).
  • Propidium Iodide (PI) and rat tail type I collagen were from Roche (Indianapolis, Ind.).
  • BMS-354825 N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate was provided by Bristol-Myers Squibb. Imatinib (Gleevec, ST1571) was provided by Novartis.
  • the A10 rat aortic smooth muscle cell line was obtained from American Type Culture Collection (Rockville, Md.) and grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 units/ml penicillin and 100 ⁇ g/ml streptomycin.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • Primary culture of human aortic smooth muscle cells (AoSMCs) was obtained from Cambrex (Walkersville, Md.) and grown in SmGM-2 Bulletkit® medium (Cambrex) plus 100 units/ml penicillin and 100 ⁇ g/ml streptomycin.
  • Human AoSMCs were used before the 7th passage. Cells were maintained at 37° C. in a humidified 95% air and 5% CO 2 incubator.
  • Cells were lysed in cold lysis buffer [25 mM Tris-HCl (pH 7.2), 150 mM NaCl, 25 mM NaF, 1 mM benzamidine, 1% Triton X-100, 1 mM Na 3 VO 4 , 20 mM p-nitrophenyl phosphate, 2 ⁇ g/ml leupeptin, 2 ⁇ g/ml aprotinin, 100 ⁇ g/ml phenylmethylsulfonyl fluoride]. Cell lysate supernatants were obtained by microcentrifugation at 4° C. for 15 min and the protein concentration was determined.
  • cell lysate supernatants were heat-denatured in SDS loading buffer.
  • Antibodies to activated STAT3, activated Akt, activated Erk1/2, and phosphotyrosine were used to assess the activation of these molecules and receptor tyrosine kinases by immunoblotting.
  • Immunoblotting was performed essentially as described previously (Cunnick et al., 2001; Cunnick et al., 2002; Ren and Wu, 2003) using the SuperSignal West Pico Chemilumiescent reagent (Pierce, Rockford, Ill.).
  • PDGFR was immunoprecipiated with an anti-PDGFR antibody (Calbiochem, PC17). Immunoprecipitates were washed twice with the lysis buffer and twice with kinase buffer [50 mM HEPES (pH 7.4), 10 mM MnCl 2 , 0.1 mM Na 3 VO 4 ]. The immune complex kinase assay was performed in 50 ⁇ l reaction mixture [kinase buffer plus 20 ⁇ Ci [ ⁇ - 32 P]-ATP, 10 ⁇ M ATP] at 30° C. for 15 min. Kinase reaction was terminated by addition of 17 ⁇ l of 4 ⁇ SDS loading buffer and heat-denaturation at 95° C. for 10 min.
  • Transwell cell migration assay (Ren et al., 2004).
  • Transwell cell culture insert polycarbonate membrane (6.5 mm, 8.0 ⁇ m pore size, Costar, Corning, N.Y.) was coated with rat tail type I collagen (10 ⁇ g/ml in PBS) at 4° C. for 18 h and air-dried.
  • VSMCs (80% confluent) were serum-starved in DMEM/0.1% BSA for 18 h, detached from plates by digestion with 1:3 diluted trypsin-EDTA (Invitrogen), washed with DMEM, and resuspended in DMEM/0.1% BSA at 5 ⁇ 10 4 cells/ml for A10 cells or 2.5 ⁇ 10 4 cells/ml for human AoSMCs.
  • Cell suspension (0.2 ml per well) was incubated with BMS-354825 or solvent (DMSO) in 1.5-ml microfuge tube for 20 min before been placed in the upper chamber of Transwell.
  • the lower chamber contained 0.6 ml DMEM/0.1% BSA with or without 5 ng/ml PDGF-BB (PeroTech, Rocky Hill, N.J.) and BMS-354825. After incubation at 37° C./5% CO 2 for 4 h, cells remaining on the upper membrane surface were mechanically removed with a cotton swab. Migrated cells on the lower side of membrane were fixed and stained with the HEMA3 reagents (Fisher Scientific, Swanee, Ga.) and enumerated under a microscope in eight randomly chosen fields with 10 ⁇ 10 lens. Each field for quantification of the migrated cell number has an area of 0.8 ⁇ 0.6 mm.
  • A10 cells and human AoSMC cells were seeded in triplicate at 2 ⁇ 10 4 per plate in 6-cm plates in DEME/1% FBS with or without PDGF-BB (10 ng/ml). After 24 h (Day 0), cells were treated with DMSO (solvent) or 10-50 nM BMS-354825. Medium was changed on Day 3. Viable cell number was determined on Day 6 as described (Dorsey et al., 2000). For the recovery experiment, cells were treated as above for 6 days and then cultured without BMS-354825 for another 6 days.
  • A10 cells (80% confluent) were serum starved in DMEM/0.1% BSA for 24 h. After which, PDGF-BB (10 ng/ml) and BMS-354825 or DMSO was added and the incubation was continued for another 16 h. Cells were collected by trypsinization and resuspended in PBS at 5 ⁇ 10 6 cells/ml. Cells were fixed in cold 70% ethanol, washed with PBS, and incubated with propidium iodide (20 ⁇ g/ml) and RNase (200 ⁇ g/ml) for 1 h at room temperature at a cell concentration of 1 ⁇ 10 6 cells/ml. Flow cytometric analysis of cell cycle phase distribution was performed using a Becton Dickinson FACSCalibur flow cytometer (Becton Dickinson, San Jose, Calif.) and 1 ⁇ 10 4 events were recorded for each sample.
  • Becton Dickinson FACSCalibur flow cytometer Becton Dickin
  • Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2. J Biol Chem 276:24380-24387.
  • BTAM bisphosphoryl tyrosine-based activation motif
  • a novel pyridopyrimidine inhibitor of abl kinase is a picomolar inhibitor of Bcr-abl-driven K562 cells and is effective against STI571-resistant Bcr-abl mutants. Clin Cancer Res 9:1267-1273.

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