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1.
Bioorg Med Chem Lett ; 26(15): 3414-20, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27394665

RESUMEN

Herein we describe our research efforts around the aryl and heteroaryl substitutions at the aminal carbon of the tetracyclic indole-based HCV NS5A inhibitor MK-8742. A series of potent NS5A inhibitors are described, such as compounds 45-47, 54, 56, and 65, which showed improved potency against clinically relevant and resistance associated HCV variants. The improved potency profiles of these compounds demonstrated an SAR that can improve the potency against GT2b, GT1a Y93H, and GT1a L31V altogether, which was unprecedented in our previous efforts in NS5A inhibition.


Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Hepacivirus/efectos de los fármacos , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Benzofuranos/síntesis química , Benzofuranos/química , Relación Dosis-Respuesta a Droga , Imidazoles/síntesis química , Imidazoles/química , Masculino , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
2.
Antimicrob Agents Chemother ; 58(2): 1167-78, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24323474

RESUMEN

The cysteine protease cruzipain is essential for the viability, infectivity, and virulence of Trypanosoma cruzi, the causative agent of Chagas disease. Thus, inhibitors of cruzipain are considered promising anti-T. cruzi chemotherapeutic agents. Reversible cruzipain inhibitors containing a nitrile "warhead" were prepared and demonstrated 50% inhibitory concentrations (IC50s) as potent as 1 nM in baculovirus-generated cruzipain enzyme assays. In epimastigote and intracellular amastigote in vitro assays, the most potent compounds demonstrated antiparasitic behavior in the 5 to 10 µM IC50 range; however, trypomastigote production from the amastigote form was ∼90 to 95% inhibited at 2 µM. Two key compounds, Cz007 and Cz008, with IC50s of 1.1 and 1.8 nM, respectively, against the recombinant enzyme were tested in a murine model of acute T. cruzi infection, with oral dosing in chow for 28 days at doses from 3 to 50 mg/kg of body weight. At 3 mg/kg of Cz007 and 3 mg/kg of Cz008, the blood parasitemia areas under the concentration-time curves were 16% and 25% of the untreated group, respectively. At sacrifice, 24 days after immunosuppression with cyclophosphamide, parasite presence in blood, heart, and esophagus was evaluated. Based on negative quantitative PCR results in all three tissues, cure rates in surviving animals were 90% for Cz007 at 3 mg/kg, 78% for Cz008 at 3 mg/kg, and 71% for benznidazole, the control compound, at 50 mg/kg.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Parasitemia/tratamiento farmacológico , Proteínas Protozoarias/antagonistas & inhibidores , Tripanocidas/farmacología , Administración Oral , Animales , Área Bajo la Curva , Enfermedad de Chagas/mortalidad , Enfermedad de Chagas/parasitología , Inhibidores de Cisteína Proteinasa/síntesis química , Concentración 50 Inhibidora , Estadios del Ciclo de Vida/efectos de los fármacos , Estadios del Ciclo de Vida/fisiología , Masculino , Ratones , Nitroimidazoles/farmacología , Parasitemia/mortalidad , Proteínas Protozoarias/metabolismo , Análisis de Supervivencia , Resultado del Tratamiento , Tripanocidas/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/fisiología
3.
Bioorg Med Chem Lett ; 21(5): 1488-92, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21295979

RESUMEN

A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC(50) of 0.34 µM) and in human whole blood assay (IC(50) of 2.1 µM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors.


Asunto(s)
Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Urea/síntesis química , Línea Celular Tumoral , Humanos , Microsomas/enzimología , Prostaglandina-E Sintasas , Relación Estructura-Actividad , Urea/química , Urea/farmacología
4.
Bioorg Med Chem Lett ; 21(3): 920-3, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21232956

RESUMEN

The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.


Asunto(s)
Catepsina K/antagonistas & inhibidores , Etilaminas/química , Inhibidores de Proteasas/química , Administración Oral , Amidas/química , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Catepsina K/metabolismo , Perros , Etilaminas/síntesis química , Etilaminas/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas
5.
Bioorg Med Chem Lett ; 20(24): 7444-9, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21041084

RESUMEN

Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease is described. The identified inhibitors bearing an amino nitrile warhead in P1 exhibit low nanomolar in vitro potency against cruzipain. Further SAR in P2 portion led to the identification of compounds, such as 26, that have a unique selectivity profile against other cysteine proteases and offering new opportunities for safer treatment of Chagas disease.


Asunto(s)
Compuestos de Bifenilo/química , Enfermedad de Chagas/tratamiento farmacológico , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/química , Valina/análogos & derivados , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/uso terapéutico , Catepsinas/antagonistas & inhibidores , Catepsinas/metabolismo , Cisteína Endopeptidasas/metabolismo , Proteasas de Cisteína/química , Proteasas de Cisteína/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/uso terapéutico , Humanos , Proteínas Protozoarias , Relación Estructura-Actividad , Valina/síntesis química , Valina/química , Valina/uso terapéutico
6.
Bioorg Med Chem Lett ; 20(2): 499-502, 2010 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-20004097

RESUMEN

A series of stearoyl-CoA desaturase 1 (SCD1) inhibitors were developed. Investigations of enzyme potency and metabolism led to the identification of the thiadiazole-pyridazine derivative MF-438 as a potent SCD1 inhibitor. MF-438 exhibits good pharmacokinetics and metabolic stability, thereby serving as a valuable tool for further understanding the role of SCD inhibition in biological and pharmacological models of diseases related to metabolic disorders.


Asunto(s)
Inhibidores Enzimáticos/síntesis química , Piridazinas/síntesis química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Tiadiazoles/síntesis química , Administración Oral , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Ratones , Microsomas Hepáticos/metabolismo , Piridazinas/química , Piridazinas/farmacocinética , Ratas , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacocinética
7.
Bioorg Med Chem Lett ; 20(3): 887-92, 2010 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-20061146

RESUMEN

MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.


Asunto(s)
Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacocinética , Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/administración & dosificación , Inhibidores de Cisteína Proteinasa/farmacocinética , Descubrimiento de Drogas/métodos , Administración Oral , Animales , Disponibilidad Biológica , Compuestos de Bifenilo/química , Catepsina K/metabolismo , Inhibidores de Cisteína Proteinasa/química , Perros , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Macaca mulatta , Conejos , Ratas
8.
Biol Chem ; 390(9): 941-8, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19453281

RESUMEN

Cathepsin K (Cat K) degrades bone type I collagen and is a target for the pharmacological treatment of osteoporosis. Further roles for Cat K have been recently described, some of which are supported by the use of purportedly selective Cat K inhibitors in human and rodent cell-based assays. Twelve commercial and non-commercial Cat K inhibitors were profiled against a panel of purified human, rat, and mouse cysteine cathepsins and in two cell-based enzyme occupancy assays for activity against Cat K, B, and L. Ten inhibitors, including the carbohydrazide Cat K inhibitor II (Boc-Phe-Leu-NHNH-CO-NHNH-Leu-Z), the non-covalent K4b, and the epoxide NC-2300, have either little Cat K selectivity, or appear poorly cell penetrant. The amino-acetonitrile-containing inhibitors L-873724 and odanacatib show greater than 100-fold human Cat K enzyme selectivity and have similar IC(50) values against each cathepsin in cell-based and enzyme assays. The basic inhibitor balicatib has greater cellular potencies than expected on the basis of purified enzyme assays. The accumulation of [(14)C]-balicatib in fibroblasts is blocked by prior treatment of the cells with NH(4)Cl, consistent with balicatib having lysosomotropic properties. These results support the use of L-873724 and odanacatib as tools to identify novel roles for Cat K using human cell-based systems, but suggest using caution in the interpretation of studies employing the other compounds.


Asunto(s)
Catepsinas/antagonistas & inhibidores , Fibroblastos/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Animales , Benzamidas/farmacología , Compuestos de Bifenilo/farmacología , Catepsina K , Línea Celular , Línea Celular Tumoral , Compuestos Epoxi/farmacología , Humanos , Hidrazinas/farmacología , Ratones , Estructura Molecular , Piperazinas/farmacología , Conejos , Ratas
10.
Bioorg Med Chem Lett ; 19(20): 5837-41, 2009 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-19748780

RESUMEN

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.


Asunto(s)
Bencimidazoles/química , Inhibidores Enzimáticos/química , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Nitrilos/química , Fenantrenos/química , Administración Oral , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Cobayas , Humanos , Hiperalgesia/tratamiento farmacológico , Oxidorreductasas Intramoleculares/metabolismo , Nitrilos/síntesis química , Nitrilos/farmacocinética , Fenantrenos/síntesis química , Fenantrenos/farmacocinética , Prostaglandina-E Sintasas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad
11.
Bioorg Med Chem Lett ; 18(3): 923-8, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18226527

RESUMEN

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.


Asunto(s)
Compuestos de Bifenilo/farmacología , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Animales , Azepinas/química , Azepinas/farmacología , Catepsina K , Colágeno/efectos de los fármacos , Colágeno/inmunología , Perros , Fibroblastos/efectos de los fármacos , Humanos , Modelos Biológicos , Estructura Molecular , Osteoporosis Posmenopáusica/tratamiento farmacológico , Piel/citología , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología
12.
Bioorg Med Chem Lett ; 17(24): 6816-20, 2007 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-18029174

RESUMEN

Phenanthrene imidazole 3 (MF63) has been identified as a novel potent, selective, and orally active mPGES-1 inhibitor. This new series was developed by lead optimization of a hit from an internal HTS campaign. Compound 3 is significantly more potent than the previously reported indole carboxylic acid 1 with an A549 whole cell IC(50) of 0.42 microM (50% FBS) and a human whole blood IC(50) of 1.3 microM. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model when orally dosed at 30 and 100mg/kg.


Asunto(s)
Analgésicos no Narcóticos/síntesis química , Imidazoles/síntesis química , Imidazoles/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Fenantrenos/síntesis química , Fenantrenos/farmacología , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/química , Analgésicos no Narcóticos/farmacología , Animales , Modelos Animales de Enfermedad , Diseño de Fármacos , Cobayas , Humanos , Hiperalgesia/inducido químicamente , Imidazoles/sangre , Imidazoles/química , Concentración 50 Inhibidora , Estructura Molecular , Fenantrenos/sangre , Fenantrenos/química , Prostaglandina-E Sintasas , Ratas , Relación Estructura-Actividad
13.
J Med Chem ; 49(3): 1066-79, 2006 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-16451072

RESUMEN

A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.


Asunto(s)
Amidas/síntesis química , Aminoacetonitrilo/análogos & derivados , Catepsinas/antagonistas & inhibidores , Ciclohexanos/síntesis química , Amidas/química , Amidas/farmacología , Aminoacetonitrilo/síntesis química , Aminoacetonitrilo/química , Aminoacetonitrilo/farmacología , Animales , Disponibilidad Biológica , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Ciclohexanos/química , Ciclohexanos/farmacología , Perros , Semivida , Masculino , Modelos Moleculares , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad
14.
Comput Struct Biotechnol J ; 14: 238-44, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27418955

RESUMEN

Within the research and development environment, higher throughput, parallelized protein purification is required for numerous activities, from small scale purification of monoclonal antibodies (mAbs) and antibody fragments for in vitro and in vivo assays to process development and optimization for manufacturing. Here, we describe specific applications and associated workflows of the Protein Maker liquid handling system utilized in both of these contexts. To meet the requirements for various in vitro assays, for the identification and validation of new therapeutic targets, small quantities of large numbers of purified antibodies or antibody fragments are often required. Reducing host cell proteins (HCP) levels following capture with Protein A by evaluating various wash buffers is an example of how parallelized protein purification can be leveraged to improve a process development outcome. Stability testing under various conditions of in-process intermediates, as an example, the mAb product from a clarified harvest, requires parallelized protein purification to generate concurrent samples for downstream assays. We have found that the Protein Maker can be successfully utilized for small-to-mid scale platform purification or for process development applications to generate the necessary purified protein samples. The ability to purify and buffer exchange up to 24 samples in parallel offers a significant reduction in time and cost per sample compared to serial purification using a traditional FPLC system. By combining the Protein Maker purification system with a TECAN Freedom EVO liquid handler for automated buffer exchange we have created a new, integrated platform for a variety of protein purification and process development applications.

15.
Diabetes ; 53(4): 1007-19, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15047616

RESUMEN

The malonyl-CoA/long-chain acyl-CoA (LC-CoA) model of glucose-induced insulin secretion (GIIS) predicts that malonyl-CoA derived from glucose metabolism inhibits fatty acid oxidation, thereby increasing the availability of LC-CoA for lipid signaling to cellular processes involved in exocytosis. For directly testing the model, INSr3 cell clones overexpressing malonyl-CoA decarboxylase in the cytosol (MCDc) in a tetracycline regulatable manner were generated, and INS(832/13) and rat islets were infected with MCDc-expressing adenoviruses. MCD activity was increased more than fivefold, and the malonyl-CoA content was markedly diminished. This was associated with enhanced fat oxidation at high glucose, a suppression of the glucose-induced increase in cellular free fatty acid (FFA) content, and reduced partitioning at elevated glucose of exogenous palmitate into lipid esterification products. MCDc overexpression, in the presence of exogenous FFAs but not in their absence, reduced GIIS in all beta-cell lines and in rat islets. It also markedly curtailed the stimulation of insulin secretion by other fuel and nonfuel secretagogues. In the absence of MCDc overexpression, the secretory responses to all types of secretagogues were amplified by the provision of exogenous fatty acids. In the presence of exogenous FFAs, the fatty acyl-CoA synthetase inhibitor triacsin C reduced secretion in response to glucose and nonfuel stimuli. The data show the existence of important links between the metabolic coupling factor malonyl-CoA, the partitioning of fatty acids, and the stimulation of insulin secretion to both fuel and nonfuel stimuli.


Asunto(s)
Acilcoenzima A/fisiología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Lípidos/fisiología , Malonil Coenzima A/metabolismo , Transducción de Señal/fisiología , Animales , Carboxiliasas/genética , Carboxiliasas/metabolismo , Células Clonales , Glucosa/farmacología , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Modelos Biológicos , Proteínas Recombinantes/metabolismo , Transfección
16.
J Med Chem ; 48(24): 7535-43, 2005 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16302795

RESUMEN

The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are approximately 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-containing analogues do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were observed in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.


Asunto(s)
Benzamidas/farmacología , Catepsinas/antagonistas & inhibidores , Lisosomas/efectos de los fármacos , Morfolinas/farmacología , Piperazinas/farmacología , Tiazoles/farmacología , Animales , Presentación de Antígeno/efectos de los fármacos , Autorradiografía , Benzamidas/química , Benzamidas/farmacocinética , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/farmacocinética , Conservadores de la Densidad Ósea/farmacología , Catepsina B/antagonistas & inhibidores , Catepsina K , Catepsina L , Línea Celular , Cisteína Endopeptidasas , Femenino , Humanos , Lisosomas/enzimología , Ratones , Ratones Endogámicos C57BL , Morfolinas/química , Piperazinas/química , Piperazinas/farmacocinética , Conejos , Ratas , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinética , Distribución Tisular
17.
J Biomol Screen ; 10(6): 599-605, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16103419

RESUMEN

Prostaglandin E2 synthase (mPGES-1), the enzyme which catalyzes the synthesis of PGE2, is induced during the inflammatory response. For this reason, mPGES-1 could be a potential therapeutic target. A high-throughput screening assay was developed to identify potential inhibitors of mPGES-1. The assay consisted of a 30-s mPGES-1 enzymatic reaction followed by the detection of PGE2 by enzyme immunoassay (EIA). The enzymatic reaction was performed in a batch mode because the instability of the substrate (10 min) limited the number of plates assayed within a working day. The detection of the product by EIA was performed on 3 instruments requiring 14 different steps for complete automation. The authors describe here the optimization and implementation of a 2-part assay on a Thermo CRS robotic system. More than 315,000 compounds were tested, and a hit rate of 0.84% was obtained for this assay. Although the entire assay required multiple steps, the assay was successfully miniaturized and automated for a high-throughput screening campaign.


Asunto(s)
Industria Farmacéutica/métodos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Animales , Automatización , Bovinos , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Técnicas para Inmunoenzimas , Prostaglandina-E Sintasas , Albúmina Sérica/metabolismo , Factores de Tiempo
18.
ACS Med Chem Lett ; 1(4): 170-4, 2010 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-24900191

RESUMEN

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

19.
J Med Chem ; 51(20): 6410-20, 2008 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-18811135

RESUMEN

Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay. Issues that arose because of metabolic demethylation of the N-methylpyrazole were addressed through introduction of a 2,2,2-trifluoroethyl substituent. This culminated in the identification of 31 (MK-1256), a potent (Cat K IC 50 = 0.62 nM) and selective (>1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F) inhibitor of cathepsin K that is efficacious in a monkey model of osteoporosis.


Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/uso terapéutico , Nitrilos/química , Osteoporosis/tratamiento farmacológico , Osteoporosis/enzimología , Pirazoles/química , Pirazoles/uso terapéutico , Sulfonas/química , Sulfonas/uso terapéutico , Animales , Catepsina K , Catepsinas/metabolismo , Inhibidores de Cisteína Proteinasa/metabolismo , Inhibidores de Cisteína Proteinasa/farmacocinética , Modelos Animales de Enfermedad , Perros , Femenino , Cinética , Macaca mulatta , Modelos Moleculares , Estructura Molecular , Pirazoles/metabolismo , Pirazoles/farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonas/metabolismo , Sulfonas/farmacocinética
20.
Bioorg Med Chem Lett ; 17(15): 4328-32, 2007 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-17544269

RESUMEN

The nitrile warhead used in a series of cathepsin K inhibitors can be replaced by a less electrophilic primary amide. The accompanying loss of potency can be partially recovered by introducing a substituent alpha to the amide. The potency gain resulting from this addition is not achieved with the nitrile derivatives due to a different geometry of the cysteine adduct in the enzyme active site. This study led to the identification of the primary amide 2g, which is an inhibitory substrate, with an IC(50) of 10 nM against cathepsin K and excellent selectivity versus the other cathepsins.


Asunto(s)
Amidas/farmacología , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Amidas/química , Catepsina K , Cromatografía Líquida de Alta Presión , Inhibidores de Cisteína Proteinasa/química , Modelos Moleculares , Estereoisomerismo
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