RESUMEN
PURPOSE: The aim of the study was to demonstrate the activity of etirinotecan pegol, a polymer conjugate of irinotecan, in multiple human tumor models and to establish both the pharmacokinetic/pharmacodynamics (PK/PD) relationship and clinical relevance of the findings. EXPERIMENTAL DESIGN: Anti-tumor activity was evaluated in mouse models of human lung, colorectal, breast, ovarian, and gastric cancers. Etirinotecan pegol was administered intravenously (once or every 3-7 days) to animals with established tumors. Activity was assessed by tumor growth delay (TGD) and regression. Mice bearing established colorectal and lung tumors were treated with etirinotecan pegol or irinotecan, and serial blood and tumor samples were collected at planned times between 0 and 60 days post-treatment for quantitation of etirinotecan pegol and SN38. For PK analysis, analyte concentration-time data were fit with compartmental models; PK/PD analysis was based on an inhibitory E max response model. RESULTS: Etirinotecan pegol was active in all tumor models. TGD was sustained for 2-10 weeks after last dose, while conventional irinotecan resulted in little suppression of tumor growth. Etirinotecan pegol was eliminated very slowly from the tumor (t 1/2 = 17 days), achieving higher and more sustained tumor exposure when compared with conventional irinotecan. The increased tumor exposure following etirinotecan pegol correlated with strong and prolonged suppression of tumor growth. Sustained plasma exposure to active SN38 was consistently observed across nonclinical species (including mouse, rat, and dog) and translated to cancer patients. CONCLUSIONS: Etirinotecan pegol is the first long-acting topoisomerase 1 inhibitor that provides sustained exposure, which results in prolonged anti-tumor activity in a wide variety of cancer models.
Asunto(s)
Antineoplásicos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Neoplasias Experimentales/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Inhibidores de Topoisomerasa I/administración & dosificación , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Perros , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Irinotecán , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias Experimentales/patología , Polietilenglicoles/farmacocinética , Polietilenglicoles/farmacología , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Inhibidores de Topoisomerasa I/farmacocinética , Inhibidores de Topoisomerasa I/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Patients with refractory angina (RA) have limited therapeutic options and significant limitations in their quality of life. Ranolazine is approved for patients with chronic stable angina but has not been studied in patients with RA. The Ranolazine Refractory Angina Registry was designed to evaluate the safety, tolerability, and effectiveness in RA patients. In a dedicated RA clinic using an extensive prospective database, 100 patients were enrolled. Angina class, medications, major adverse cardiac events including death, myocardial infarction, and revascularization were obtained at 1, 6, and 12 months. Overall 43% of patients had a ≥2 class improvement in angina. At 1 year, 57% patients remained on ranolazine (91.2%; 500 mg BID), including 58% with a ≥2 class improvement in angina. Reasons for discontinuation included: side effects (n = 16), major adverse cardiac events (n = 10), cost (n = 5), ineffective (n = 6), cost and ineffective (n = 3), and unknown (n = 3). In conclusion, ranolazine is an effective antianginal therapy in patients with RA; still at 1 year only 57% of patients remained on ranolazine because of side effects, suboptimal effectiveness, cost, or progression of disease.
Asunto(s)
Acetanilidas , Angina de Pecho , Piperazinas , Acetanilidas/administración & dosificación , Acetanilidas/efectos adversos , Anciano , Angina de Pecho/diagnóstico , Angina de Pecho/tratamiento farmacológico , Angina de Pecho/fisiopatología , Interpretación Estadística de Datos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Pacientes Desistentes del Tratamiento , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Vigilancia de Productos Comercializados/métodos , Vigilancia de Productos Comercializados/estadística & datos numéricos , Ranolazina , Sistema de Registros/estadística & datos numéricos , Resultado del Tratamiento , Estados UnidosRESUMEN
AIMS: An increasing number of patients with severe coronary artery disease (CAD) are not candidates for traditional revascularization and experience angina in spite of excellent medical therapy. Despite limited data regarding the natural history and predictors of adverse outcome, these patients have been considered at high risk for early mortality. METHODS AND RESULTS: The OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) program at the Minneapolis Heart Institute offers traditional and investigational therapies for patients with refractory angina. A prospective clinical database includes detailed baseline and yearly follow-up information. Death status and cause were determined using the Social Security Death Index, clinical data, and death certificates. Time to death was analysed using survival analysis methods. For 1200 patients, the mean age was 63.5 years (77.5% male) with 72.4% having prior coronary artery bypass grafting, 74.4% prior percutaneous coronary intervention, 72.6% prior myocardial infarction, 78.3% 3-vessel CAD, 23.0% moderate-to-severe left-ventricular (LV) dysfunction, and 32.6% congestive heart failure (CHF). Overall, 241 patients died (20.1%: 71.8% cardiovascular) during a median follow-up 5.1 years (range 0-16, 14.7% over 9). By Kaplan-Meier analysis, mortality was 3.9% (95% CI 2.8-5.0) at 1 year and 28.4% (95% CI 24.9-32.0) at 9 years. Multivariate predictors of all-cause mortality were baseline age, diabetes, angina class, chronic kidney disease, LV dysfunction, and CHF. CONCLUSION: Long-term mortality in patients with refractory angina is lower than previously reported. Therapeutic options for this distinct and growing group of patients should focus on angina relief and improved quality of life.
Asunto(s)
Angina de Pecho/mortalidad , Adulto , Anciano , Angina de Pecho/terapia , Causas de Muerte , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Minnesota/epidemiología , Infarto del Miocardio/mortalidad , Estudios Prospectivos , Disfunción Ventricular Izquierda/mortalidadRESUMEN
OBJECTIVES: To determine the contemporary prevalence of and mortality in patients with coronary artery disease (CAD) not amenable to revascularization. BACKGROUND: A growing number of patients have severe CAD with ongoing angina despite optimal medical therapy which is not amenable to traditional revascularization. Limited data exist on contemporary prevalence and outcome for these patients. METHODS: Clinical and angiographic data were reviewed for 493 consecutive patients undergoing coronary angiography and revascularization if indicated. Patients were categorized into six groups: (1) normal coronary arteries, (2) CAD <70%, (3) CAD >70% with complete revascularization by percutaneous intervention or coronary artery bypass grafting, (4) CAD >70% with partial revascularization, (5) CAD >70% treated medically, and (6) CAD >70% on optimal medical therapy with no revascularization option. All-cause mortality at 3 years was determined. RESULTS: Prevalence for groups 1-6 was 14.8, 19.5, 36.9, 12.8, 9.3, and 6.7%, respectively. Three-year mortality increased with angiographic severity of CAD: 2.7, 6.3, 8.2, 12.7, 17.4, and 15.2%, respectively. Patients with incomplete revascularization (groups 4-6, n = 142) had higher mortality than completely revascularized patients (groups 1-3, n = 351): 14.8 vs. 6.6% (P = 0.004). CONCLUSIONS: In a contemporary series of patients undergoing coronary angiography, 28.8% (142/493) of patients had significant CAD and did not undergo complete revascularization, including 12.8% partially revascularized, 9.3% managed medically, and 6.7% with "no-option." These patients had higher mortality at 3 years (14.8 vs. 6.6%, P = 0.004) when compared with completely revascularized patients.
Asunto(s)
Enfermedad de la Arteria Coronaria/mortalidad , Anciano , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Revascularización Miocárdica , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
In recent years, improvements in both pharmacologic and revascularization therapies have greatly increased life expectancy for patients with coronary artery disease (CAD). As patients with more extensive CAD live longer, many develop myocardial ischemia and clinical angina that is not amenable to traditional revascularization therapy. Patients with severe, symptomatic, chronic CAD have been described as having refractory angina; they have also been termed "no-option" patients. This article discusses clinical management of this unique and growing group of patients and emerging therapeutic options including pharmacologic agents, enhanced external counterpulsation therapy, therapeutic angiogenesis, neurostimulation, and transmyocardial revascularization.
Asunto(s)
Angina de Pecho/terapia , Enfermedad Coronaria/terapia , Reestenosis Coronaria/terapia , Infarto del Miocardio/terapia , Angina de Pecho/mortalidad , Angioplastia Coronaria con Balón , Puente de Arteria Coronaria , Enfermedad Coronaria/mortalidad , Reestenosis Coronaria/mortalidad , Contrapulsación , Femenino , Predicción , Humanos , Persona de Mediana Edad , Minnesota , Infarto del Miocardio/mortalidad , Recurrencia , Investigación/tendencias , Stents , Tasa de SupervivenciaRESUMEN
High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Furanos/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Tiazoles/síntesis química , Tiofenos/síntesis química , Triazoles/síntesis química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Capilares/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/citología , Furanos/química , Furanos/farmacología , Técnicas In Vitro , Masculino , Modelos Moleculares , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Tiofenos/química , Tiofenos/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human and mouse endothelial cell growth. Using a mouse matrigel model, this reversible hMetAP2 inhibitor was also shown to inhibit angiogenesis in vivo.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Triazoles/síntesis química , Aminopeptidasas/química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cobalto/metabolismo , Colágeno , Cristalografía por Rayos X , Combinación de Medicamentos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/citología , Activación Enzimática , Humanos , Laminina , Metaloendopeptidasas/química , Ratones , Modelos Moleculares , Estructura Molecular , Proteoglicanos , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
Tie2 kinase, an enzyme that supports angiogenesis essential for tumor growth and survival, was selected as a target in a search for naturally occurring inhibitors of potential utility for antitumor therapy. Two polybrominated diphenyl ethers, 3,5-dibromo-2-(2',4'-dibromophenoxy)phenol (1) and 4,6-dibromo-2-(2',4'-dibromophenoxy)phenol (2) were isolated from an extract prepared from Dysidea sp. after bioassay-guided fractionation.
Asunto(s)
Bifenilos Polibrominados/aislamiento & purificación , Poríferos/química , Receptor TIE-2/antagonistas & inhibidores , Animales , Éteres/química , Espectroscopía de Resonancia Magnética , Bifenilos Polibrominados/farmacologíaRESUMEN
Bioassay-guided fractionation of an active organic extract of Piper caninum, using a sensitive yeast assay to monitor putative double-strand DNA-damaging activity, resulted in the isolation of the 4,5-dioxoaporphine alkaloid cepharadione A (1). Compound 1 exhibited potent inhibitory activity in a yeast cytotoxicity assay with IC(50) values of 50.2 nM toward RS321NpRAD52 grown on glucose versus 293 nM toward the same yeast strain grown on galactose.
Asunto(s)
Alcaloides/aislamiento & purificación , Aporfinas/aislamiento & purificación , Daño del ADN , Piper/química , Plantas Medicinales/química , Alcaloides/química , Alcaloides/farmacología , Aporfinas/química , Aporfinas/farmacología , Indonesia , Concentración 50 Inhibidora , Estructura Molecular , Tallos de la Planta/química , Saccharomyces cerevisiae/efectos de los fármacosRESUMEN
We describe a case of rotational atherectomy (RA) used in the setting of extensive coronary dissection. Unsuccessful predilitation of a heavily calcified proximal LAD stenosis resulted in balloon rupture, which produced occlusive dissection extending into the mid LAD. Limited options for this patient required that we perform RA to permit stent delivery and deployment and avoid anterior myocardial infarction. A brief discussion of reasons for balloon angioplasty failure and the potential role for subsequent RA is given. Predictors for coronary perforation when performing RA are reviewed. Our rationale and strategy to avoid the increased risk of perforation with RA in this contraindicated setting of extensive dissection is given.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/instrumentación , Aterectomía Coronaria/métodos , Reestenosis Coronaria/terapia , Estenosis Coronaria/diagnóstico por imagen , Anciano , Angioplastia Coronaria con Balón/métodos , Calcinosis/diagnóstico por imagen , Calcinosis/terapia , Angiografía Coronaria/métodos , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/etiología , Estenosis Coronaria/terapia , Vasos Coronarios/lesiones , Falla de Equipo , Femenino , Estudios de Seguimiento , Humanos , Medición de Riesgo , Rotura Espontánea/diagnóstico por imagen , Rotura Espontánea/etiología , Rotura Espontánea/cirugía , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Grado de Desobstrucción VascularRESUMEN
Bioassay-guided fractionation of a CH(2)Cl(2)-MeOH extract of the twigs of Coussarea paniculata using a yeast-based assay for potential DNA-damaging agents resulted in the isolation of three new lupane triterpenoids, 1-3, in addition to eight known triterpenoids, lupeol (4), lupeyl acetate (5), betulin (6), betulinic acid (7), 3-epi-betulinic acid (8), 3-epi-betulinaldehyde (9), oleanolic acid (10), and ursolic acid (11). The structures of the new compounds were established as lup-20(29)-en-3beta,25-diol (1), lup-20(29)-en-11alpha-ol-25,3beta-lactone (2), and 3-deoxybetulonic acid (3), on the basis of extensive 1D and 2D NMR spectroscopic data interpretation and chemical conversion.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Plantas Medicinales/química , Rubiaceae/química , Triterpenos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Guyana , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Neoplasias Ováricas , Tallos de la Planta/química , Estereoisomerismo , Triterpenos/química , Triterpenos/farmacología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
A strain of yeast rendered repair deficient by the conditional expression of the RAD52 locus was used to search for natural products capable of damaging DNA. Four ellagic acid derivatives, namely 3,3'-dimethyl-4'-O-beta-D-glucopyranosyl ellagic acid (1), 3,3',4-trimethyl-4'-O-beta-D-glucopyranosyl ellagic acid (2), 3'-methyl-3,4-O,O-methylidene ellagic acid (3) and 3'-methyl-3,4-O,O-methylidene-4'-O-beta-D-glucopyranosyl ellagic acid (4), were identified by this assay as DNA damaging natural principles from several plants, including Alangium javanicum, Anisophyllea apetala, Crypteronia paniculata, Mouririi sp. and Scholtzia parviflora. Although none of the isolated principles mediated frank strand scission of DNA in vitro, all of them potently inhibited the growth of yeast in the absence of expression of RAD52.
Asunto(s)
Daño del ADN/efectos de los fármacos , Ácido Elágico/análogos & derivados , Ácido Elágico/farmacología , Bioensayo , ADN Superhelicoidal/efectos de los fármacos , Ácido Elágico/síntesis química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plantas/química , Saccharomyces cerevisiae/genética , Relación Estructura-ActividadRESUMEN
A survey of crude plant extracts using a new yeast strain designed to identify DNA-damaging agents resulted in the identification of an extract prepared from Crypteronia paniculata. Bioassay-guided fractionation resulted in the isolation of three active compounds. Two of these were ellagic acid derivatives, namely, 3,3'-di-O-methylellagic acid 4'-O-beta-d-xylopyranoside (1) and 3'-O-methyl-3,4-methylenedioxyellagic acid 4'-O-beta-d-glucopyranoside (2). The third was identified as kaempferol-3-O-alpha-l-rhamnoside (3). The three principles exhibited strong, selective cytotoxity toward the RAD52 repair-deficient yeast strain.
Asunto(s)
Antifúngicos/aislamiento & purificación , Daño del ADN , ADN/efectos de los fármacos , Ácido Elágico/aislamiento & purificación , Flavonoides/aislamiento & purificación , Glicósidos/aislamiento & purificación , Quempferoles , Extractos Vegetales/química , Plantas Medicinales/química , Saccharomyces cerevisiae/efectos de los fármacos , Antifúngicos/química , Antifúngicos/farmacología , Proteínas de Unión al ADN/efectos de los fármacos , Ácido Elágico/análogos & derivados , Ácido Elágico/química , Ácido Elágico/farmacología , Flavonoides/química , Flavonoides/farmacología , Glicósidos/química , Glicósidos/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Filipinas , Proteína Recombinante y Reparadora de ADN Rad52 , Proteínas de Saccharomyces cerevisiaeRESUMEN
Interleukin (IL)-18 has profound antitumor activity when administered at high doses as a single agent for prolonged periods in BALB/c mice bearing late, well-established MOPC-315 tumors. Management with a qD x 27 schedule resulted in regression of tumors in all animals receiving 5 mg/kg/d. A protracted daily management regimen appears to be necessary to induce regression in this advanced tumor model. Biologic markers were assessed and appear to be potentially useful in evaluating the immunologic and antitumor activity of IL-18. The biomarkers of IL-18's immunologic activity include, but are not limited to, IL-1alpha, IL-2, IL-8, IL-10, IL-12, IL-13, interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor. The profile of these circulating cytokines and their expression levels at baseline, and after IL-18 delivery, can be measured in the serum, as well as from splenocytes of mice or human peripheral blood mononuclear cells derived from either normal subjects or patients with cancer. We compared IL-18 and IL-12 alone or in combination for their ability to induce cytokine production and natural killer cytolytic activity. Our data support the notion that IL-18 induces a predominantly Th1 response, and that the mechanism of IL-18 activity differs from that of IL-12. The biologic activity of IL-18 management revealed by increases in serum levels of cytokines and enhancement of natural killer cytolytic activity will be useful as clinical trials initiate in 2002. Expression of interferon-gamma and granulocyte-macrophage colony-stimulating factor serum levels correlates directly over a broad dose escalation with the level of IL-18. Therefore, this provides a convenient pharmacodynamic reference to the biologic response to IL-18 that may serve to guide the conduct of clinical trials.
Asunto(s)
Citocinas/metabolismo , Inmunidad Celular/efectos de los fármacos , Interleucina-12/farmacología , Interleucina-18/farmacología , Plasmacitoma/tratamiento farmacológico , Células TH1/efectos de los fármacos , Animales , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Recombinación Genética , Valores de Referencia , Sensibilidad y Especificidad , Células TH1/inmunologíaRESUMEN
A MeOH/CH(2)Cl(2) extract of the bud covers of Artocarpus altilis collected in Micronesia showed activity in a cathepsin K inhibition assay. In addition to the three known flavonoids isolated from the bud covers of this species, two new compounds have been identified whose structures were determined on the basis of spectral data. These compounds include a dimeric dihydrochalcone, cycloaltilisin 6 (2), and a new prenylated flavone, cycloaltilisin 7 (3). Novel compounds 2 and 3 have IC(50) values of 98 and 840 nM, respectively, in cathepsin inhibition.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Chalcona/aislamiento & purificación , Inhibidores de Cisteína Proteinasa/aislamiento & purificación , Flavonoides/aislamiento & purificación , Moraceae/química , Catepsina K , Chalcona/análogos & derivados , Chalcona/química , Chalcona/farmacología , Cromatografía Líquida de Alta Presión , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Flavonoides/química , Flavonoides/farmacología , Concentración 50 Inhibidora , Micronesia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Plantas Medicinales , Espectrofotometría InfrarrojaRESUMEN
As part of a search for novel inhibitors of cathepsin K, the MeOH extract of a Micronesian sponge of the order Haplosclerida was shown to be active. Bioassay-guided fractionation of the extract yielded halitoxins, tryptamine, and a novel tryptamine-derived alkaloid, haploscleridamine (1). The tetrahydro-beta-carboline structure of haploscleridamine (1) was elucidated through spectral techniques. Haploscleridamine (1) was found to be an inhibitor of cathepsin K with an IC(50) of 26 microM.