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1.
Front Chem ; 10: 1090643, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36700083

RESUMEN

Protein-protein interactions (PPIs) are recognized as important targets in drug discovery. The characteristics of molecules that inhibit PPIs differ from those of small-molecule compounds. We developed a novel chemical library database system (DLiP) to design PPI inhibitors. A total of 32,647 PPI-related compounds are registered in the DLiP. It contains 15,214 newly synthesized compounds, with molecular weight ranging from 450 to 650, and 17,433 active and inactive compounds registered by extracting and integrating known compound data related to 105 PPI targets from public databases and published literature. Our analysis revealed that the compounds in this database contain unique chemical structures and have physicochemical properties suitable for binding to the protein-protein interface. In addition, advanced functions have been integrated with the web interface, which allows users to search for potential PPI inhibitor compounds based on types of protein-protein interfaces, filter results by drug-likeness indicators important for PPI targeting such as rule-of-4, and display known active and inactive compounds for each PPI target. The DLiP aids the search for new candidate molecules for PPI drug discovery and is available online (https://skb-insilico.com/dlip).

2.
Org Lett ; 22(20): 8039-8043, 2020 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-33006475

RESUMEN

Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for the production of peptide therapeutics and diagnostics containing N-methylamino acids.


Asunto(s)
Anhídridos/química , Indicadores y Reactivos/química , Péptidos/química , Aminoácidos , Estructura Molecular , Estereoisomerismo
3.
ChemMedChem ; 14(14): 1305-1314, 2019 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-31066983

RESUMEN

Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Herein we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds (including the worldwide highest resolutions for Hdm2 and HdmX, at 1.13 and 1.20 Å, respectively). We also reveal the key additive 18-crown-ether, which we discovered to enable HdmX crystallization and show its stabilization of various Lys residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insight into the possible adaptations and structural states of Hdm2 (e.g., flip of F55, flip of Y67, reorientation of H96) and HdmX (e.g., flip of H55, dimer induction), enabling key binding interactions for different compound classes. To facilitate comparisons, we used the same numbering for Hdm2 (as in Q00987) and HdmX (as in O15151, but minus 1). Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Compuestos Heterocíclicos/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Sitios de Unión , Proteínas de Ciclo Celular/química , Cristalografía por Rayos X , Compuestos Heterocíclicos/química , Humanos , Unión Proteica , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas c-mdm2/química
4.
Bioorg Med Chem Lett ; 28(20): 3404-3408, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30217415

RESUMEN

Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.


Asunto(s)
Antineoplásicos/farmacología , Multimerización de Proteína/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirazoles/farmacología , Pirrolidinonas/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Perros , Haplorrinos , Humanos , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Pirrolidinonas/farmacocinética , Ratas Sprague-Dawley , Estereoisomerismo
7.
Bioorg Med Chem Lett ; 26(19): 4837-4841, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27542305

RESUMEN

The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.


Asunto(s)
Descubrimiento de Drogas , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Conformación Molecular , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
8.
Bioorg Med Chem Lett ; 25(17): 3621-5, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26141769

RESUMEN

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.


Asunto(s)
Isoquinolinas/química , Isoquinolinas/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Cristalografía por Rayos X , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
9.
J Med Chem ; 58(16): 6348-58, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26181851

RESUMEN

As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Ensayos Clínicos Fase I como Asunto , Descubrimiento de Drogas , Humanos , Isoquinolinas/farmacocinética , Piperazinas/farmacocinética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Elife ; 42015 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-25965177

RESUMEN

Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53-HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53-HDM2 inhibitors, such as NVP-CGM097.


Asunto(s)
Biomarcadores/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Isoquinolinas/farmacología , Neoplasias/tratamiento farmacológico , Selección de Paciente , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Transferencia Resonante de Energía de Fluorescencia , Perfilación de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
11.
Bioorg Med Chem Lett ; 24(9): 2110-4, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24704029

RESUMEN

Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
12.
Bioorg Med Chem Lett ; 22(10): 3498-502, 2012 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-22507962

RESUMEN

Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction.


Asunto(s)
Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Valina/metabolismo , Modelos Moleculares , Unión Proteica , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores
13.
Bioorg Med Chem Lett ; 20(12): 3628-31, 2010 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-20483608

RESUMEN

A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies toward activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency.


Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Administración Oral , Animales , Humanos , Interleucina-2/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones , Microsomas Hepáticos/metabolismo , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad
15.
Curr Top Med Chem ; 10(7): 752-66, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20337583

RESUMEN

The recent emergence of osteoporosis as a major health threat in people of advanced age has intensified the search for novel and effective pharmacologic treatments. Given that bone resorption is exceeding bone formation, a reduction in bone mass leads to disease conditions including post-menopausal osteoporosis and tumor-induced osteolysis. Our efforts in this area have focused on the optimization of non-peptidic cathepsin K inhibitors for affinity and selectivity, from an heteroaromatic nitrile as a novel scaffold. This approach has resulted in the discovery of the potent and selective cathepsin K inhibitor, 44. The concentration of cathepsin K inhibitors, including compound 44, in the target tissues such as bone marrow cavity, were predictive parameters for antibone resorptive efficacy in vivo in the rat. The high level of distribution to the bone marrow was also observed for compounds containing pyrrolopyrimidines with novel spiro-structures as the P3 moiety. In a monkey study with the representative inhibitor 44, the antibone resorptive efficacy was detected 8 h after the compound administration. The efficacy persisted throughout the repeated treatment period of 14 days without any evidence for the development of tolerance. This article constitutes a near comprehensive review of the published scientific literature on small molecule non-peptidic inhibitors for cathepsin K developed by Novartis.


Asunto(s)
Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacocinética , Pirimidinas/síntesis química , Pirroles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Catepsina K/química , Catepsina K/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Humanos , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Relación Estructura-Actividad
16.
Expert Opin Ther Pat ; 20(4): 563-82, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20302452

RESUMEN

IMPORTANCE OF THE FIELD: Bones play many roles in the body, providing structure, protecting organs, anchoring muscles and storing calcium. Over 100 million people worldwide suffer from bone diseases, mainly osteoporosis, cancer-related bone loss, osteoarthritis and inflammatory arthritis. Osteoporosis itself has no specific symptoms, and the main consequence is the increased risk of bone fractures. Therefore, the prevention of bone diseases is important to maintain the quality of life in the human society. However, treatment options are still insufficient. AREAS COVERED IN THIS REVIEW: This review article gives a summary of the low molecular mass modulators of bone diseases targets disclosed in patent applications and articles, mainly during the last 5 years. WHAT THE READER WILL GAIN: Readers will rapidly gain an overview of these modulators not only for historical targets, but also of emerging and re-visited targets. Readers will also be able to see the current research trend and the main players in this field. TAKE HOME MESSAGE: Drug discovery for bone diseases has made progress in the last years. The research area has dynamically shifted from historical targets (bisphosphonate, parathyroid hormone and calcitonin) to newly confirmed targets or targets re-visited which were biologically validated in the past. Cathepsin K inhibitors should be very close to launching in the market.


Asunto(s)
Enfermedades Óseas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Animales , Enfermedades Óseas/fisiopatología , Descubrimiento de Drogas/métodos , Humanos , Patentes como Asunto , Calidad de Vida
17.
Methods Mol Biol ; 575: 173-94, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19727615

RESUMEN

Chemogenomics knowledge-based drug discovery approaches aim to extract the knowledge gained from one target and to apply it for the discovery of ligands and hopefully drugs of a new target which is related to the parent target by homology or conserved molecular recognition. Herein, we demonstrate the potential of knowledge-based virtual screening by applying it to the MDM4-p53 protein-protein interaction where the MDM2-p53 protein-protein interaction constitutes the parent reference system; both systems are potentially relevant to cancer therapy. We show that a combination of virtual screening methods, including homology based similarity searching, QSAR (Quantitative Structure-Activity Relationship) methods, HTD (High Throughput Docking), and UNITY pharmacophore searching provide a successful approach to the discovery of inhibitors. The virtual screening hit list is of the magnitude of 50,000 compounds picked from the corporate compound library of approximately 1.2 million compounds. Emphasis is placed on the facts that such campaigns are only feasible because of the now existing HTCP (High throughput Cherry-Picking) automation systems in combination with robust MTS (Medium Throughput Screening) fluorescence-based assays. Given that the MDM2-p53 system constitutes the reference system, it is not surprising that significantly more and stronger hits are found for this interaction compared to the MDM4-p53 system. Novel, selective and dual hits are discovered for both systems. A hit rate analysis will be provided compared to the full HTS (High-throughput Screening).


Asunto(s)
Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Bases del Conocimiento , Proteínas Nucleares/química , Mapeo de Interacción de Proteínas/estadística & datos numéricos , Proteínas Proto-Oncogénicas/química , Proteína p53 Supresora de Tumor/química , Proteínas de Ciclo Celular , Árboles de Decisión , Descubrimiento de Drogas/estadística & datos numéricos , Ensayos Analíticos de Alto Rendimiento/estadística & datos numéricos , Humanos , Modelos Moleculares , Biología Molecular/métodos , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad Cuantitativa , Homología Estructural de Proteína , Proteína p53 Supresora de Tumor/metabolismo , Interfaz Usuario-Computador
18.
J Biol Chem ; 284(13): 8812-21, 2009 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-19153082

RESUMEN

p53 tumor suppressor activity is negatively regulated through binding to the oncogenic proteins Hdm2 and HdmX. The p53 residues Leu(26), Trp(23), and Phe(19) are crucial to mediate these interactions. Inhibiting p53 binding to both Hdm2 and HdmX should be a promising clinical approach to reactivate p53 in the cancer setting, but previous studies have suggested that the discovery of dual Hdm2/HdmX inhibitors will be difficult. We have determined the crystal structures at 1.3 A of the N-terminal domain of HdmX bound to two p53 peptidomimetics without and with a 6-chlorine substituent on the indole (which binds in the same subpocket as Trp(23) of p53). The latter compound is the most potent peptide-based antagonist of the p53-Hdm2 interaction yet to be described. The x-ray structures revealed surprising conformational changes of the binding cleft of HdmX, including an "open conformation" of Tyr(99) and unexpected "cross-talk" between the Trp and Leu pockets. Notably, the 6-chloro p53 peptidomimetic bound with high affinity to both HdmX and Hdm2 (K(d) values of 36 and 7 nm, respectively). Our results suggest that the development of potent dual inhibitors for HdmX and Hdm2 should be feasible. They also reveal possible conformational states of HdmX, which should lead to a better prediction of its interactions with potential biological partners.


Asunto(s)
Materiales Biomiméticos/química , Complejos Multiproteicos/química , Proteínas Nucleares/química , Péptidos/química , Proteínas Proto-Oncogénicas/química , Proteína p53 Supresora de Tumor/química , Sitios de Unión/fisiología , Materiales Biomiméticos/metabolismo , Proteínas de Ciclo Celular , Cristalografía por Rayos X , Humanos , Complejos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Péptidos/metabolismo , Unión Proteica/fisiología , Estructura Cuaternaria de Proteína/fisiología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
19.
Bioorg Med Chem Lett ; 18(19): 5280-4, 2008 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-18783943

RESUMEN

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.


Asunto(s)
Catepsinas/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Catepsina L , Técnicas Químicas Combinatorias , Cisteína Endopeptidasas , Humanos , Masculino , Estructura Molecular , Esclerosis Múltiple/tratamiento farmacológico , Dolor/tratamiento farmacológico , Pirimidinas/sangre , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
20.
J Med Chem ; 51(17): 5459-62, 2008 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-18707091

RESUMEN

On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.


Asunto(s)
Resorción Ósea/tratamiento farmacológico , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Animales , Médula Ósea/metabolismo , Catepsina K , Colágeno Tipo I/metabolismo , Haplorrinos , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Ratas , Compuestos de Espiro , Distribución Tisular
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