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1.
Nature ; 550(7677): 481-486, 2017 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-29045389

RESUMEN

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.


Asunto(s)
Piperidinas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Peptidasa Específica de Ubiquitina 7/antagonistas & inhibidores , Animales , Apoenzimas/antagonistas & inhibidores , Apoenzimas/química , Apoenzimas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , Humanos , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Piperidinas/síntesis química , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirazoles/síntesis química , Pirimidinas/síntesis química , Especificidad por Sustrato , Transcripción Genética/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Peptidasa Específica de Ubiquitina 7/química , Peptidasa Específica de Ubiquitina 7/metabolismo , Ubiquitinación/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Bioorg Med Chem Lett ; 27(4): 1062-1069, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28131713

RESUMEN

Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.


Asunto(s)
Canal de Potasio Kv1.5/antagonistas & inhibidores , Piridinas/farmacología , Descubrimiento de Drogas , Humanos , Piridinas/farmacocinética , Relación Estructura-Actividad
3.
Bioorg Med Chem Lett ; 26(7): 1803-8, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-26927423

RESUMEN

The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.


Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/química , Piridonas/farmacología , Bencimidazoles/síntesis química , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Janus Quinasa 1/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Piridonas/síntesis química , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 24(6): 1466-71, 2014 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-24582987

RESUMEN

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.


Asunto(s)
Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Sulfonamidas/química , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Animales , Sitios de Unión , Evaluación Preclínica de Medicamentos , Semivida , Janus Quinasa 2/metabolismo , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Piridonas/síntesis química , Piridonas/farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética
5.
Elife ; 102021 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-34636321

RESUMEN

Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient's 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.


Asunto(s)
Proteínas de Unión al ADN/genética , Eliminación de Gen , Neoplasias Pulmonares/genética , Neoplasias de Células Escamosas/genética , Factores de Transcripción/genética , Ubiquitina Tiolesterasa/genética , Animales , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Factores de Transcripción/metabolismo , Ubiquitina Tiolesterasa/metabolismo
8.
J Med Chem ; 63(4): 1612-1623, 2020 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-31971798

RESUMEN

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.


Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Quinolonas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Femenino , Humanos , Isocitrato Deshidrogenasa/metabolismo , Ratones Endogámicos BALB C , Estructura Molecular , Unión Proteica , Piridinas/síntesis química , Piridinas/metabolismo , Quinolinas/síntesis química , Quinolinas/metabolismo , Quinolonas/síntesis química , Quinolonas/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Org Chem ; 74(22): 8866-9, 2009 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-19845317

RESUMEN

A bench-stable potassium trifluoroborate enol ether reagent has been prepared. This reagent is suitable for the incorporation of 2,2-difluoroenolethers into aryl and heteroaryl systems via palladium-mediated cross-coupling with suitable halide coupling partners.


Asunto(s)
Boratos/química , Éteres/síntesis química , Cetonas/síntesis química , Paladio/química , Éteres/química , Cetonas/química , Estructura Molecular , Sales (Química)/química , Estereoisomerismo
10.
J Pharmacol Exp Ther ; 324(1): 322-30, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17967939

RESUMEN

Drug discovery efforts have focused recently on atrial-selective targets, including the Kv1.5 channel, which underlies the ultrarapid delayed rectifier current, I(Kur), to develop novel treatments for atrial fibrillation (AF). Two structurally distinct compounds, a triarylethanolamine TAEA and an isoquinolinone 3-[(dimethylamino)-methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (ISQ-1), blocked I(Kur) in Chinese hamster ovary cells expressing human Kv1.5 with IC(50) values of 238 and 324 nM, respectively. In anesthetized dogs, i.v. infusions of TAEA and ISQ-1 elicited comparable 16% increases in atrial refractory period, with no effect on ventricular refractory period or QTc interval. Plasma concentrations at end infusion for TAEA and ISQ-1 were 58.5 +/- 23.6 and 330.3 +/- 43.5 nM, respectively. The abilities of TAEA and ISQ-1 to terminate AF, with comparison to the rapidly activating component of delayed rectifier potassium current blocker (+)-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride (MK-499) and the class IC 1-[2-[2-hydroxy-3-(propylamino)-propoxy]phenyl]-3-phenyl-1-propanone (propafenone), were assessed in conscious dogs with heart failure and inducible AF (entry criterion). All test agents administered in i.v. bolus regimens terminated AF in at least half of animals tested; conversely no agent was universally effective. MK-499, ISQ-1, TAEA, and propafenone terminated AF in five of six, four of seven, four of six, and five of six animals at plasma concentrations of 32.6 +/- 18.7, 817 +/- 274, 714 +/- 622, and 816 +/- 240 nM, respectively. Directed cardiac electrophysiologic studies in anesthetized dogs using i.v. bolus (consistent with AF studies) plus infusion regimens with TAEA and ISQ-1 demonstrated significant increases in atrial refractory period (12-15%), A-H and P-A intervals, but no effects on ventricular refractory period, H-V, and HEG intervals. The demonstration of AF termination with TAEA and ISQ-1 in the dog heart failure model extends the profile of antiarrhythmic efficacy of Kv1.5 blockade.


Asunto(s)
Antiarrítmicos/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/uso terapéutico , Piridinas/uso terapéutico , Animales , Fibrilación Atrial/fisiopatología , Benzopiranos/uso terapéutico , Línea Celular , Perros , Femenino , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Humanos , Masculino , Piperidinas/uso terapéutico , Propafenona/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico
11.
J Med Chem ; 60(23): 9676-9690, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-29156136

RESUMEN

The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.


Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirazoles/farmacología , Animales , Perros , Descubrimiento de Drogas , Halogenación , Humanos , Janus Quinasa 1/química , Janus Quinasa 1/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Ratas , Relación Estructura-Actividad
12.
J Med Chem ; 49(24): 6954-7, 2006 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-17125248

RESUMEN

Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in in vitro and in vivo assays for inhibition of the Kv1.5 potassium channel and its associated cardiac potassium current, IKur. Structural modifications of isoquinolinone lead 1 afforded compounds with excellent potency, selectivity, and oral bioavailability.


Asunto(s)
Antiarrítmicos/síntesis química , Fibrilación Atrial/tratamiento farmacológico , Isoquinolinas/síntesis química , Canal de Potasio Kv1.5/antagonistas & inhibidores , Nitrilos/síntesis química , Administración Oral , Animales , Antiarrítmicos/química , Antiarrítmicos/farmacología , Disponibilidad Biológica , Electrofisiología , Corazón/efectos de los fármacos , Corazón/fisiología , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Canal de Potasio Kv1.5/fisiología , Nitrilos/química , Nitrilos/farmacología , Técnicas de Placa-Clamp , Ratas , Estereoisomerismo , Relación Estructura-Actividad
13.
Curr Top Med Chem ; 3(10): 1075-93, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12769709

RESUMEN

The development of farnesyltransferase inhibitors, a novel approach to non-cytotoxic anticancer therapy, has been an active area of research over the past decade. Compounds that have advanced to clinical trials were evolved both from substrate-based design efforts and from compound library screening hits. This review focuses on the effort at Merck to evolve inhibitors from the protein substrate of farnesyltransferase, which resulted in the identification of a non-peptide inhibitor for clinical evaluation. X-ray crystal structures of farnesyltransferase complexed with early peptidomimetic as well as later non-peptide inhibitors have validated this design approach. NMR spectroscopic methods for studying enzyme-bound inhibitor structure, in conjunction with the use of conformational constraints, were critical components of subsequent efforts to provide potent inhibitors with varying levels of farnesyltransferase and geranylgeranyltransferase-I inhibitory specificity. Several of these compounds were important tools for investigating the use of prenyltransferase inhibitors to target Ki-Ras-mediated tumor growth.


Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Antineoplásicos/química , Inhibidores Enzimáticos/química , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Ensayos Clínicos como Asunto , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Farnesiltransferasa , Humanos , Estructura Molecular , Neoplasias/enzimología , Prenilación de Proteína , Relación Estructura-Actividad
14.
Org Lett ; 4(7): 1201-4, 2002 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-11922818

RESUMEN

[reaction: see text] A one-pot, tandem reductive amination-transamidation-cyclization reaction was employed to produce substituted piperazin-2-ones in good yields. Various amino acid methyl esters and transferable acyl groups were examined to establish the reaction's scope.


Asunto(s)
Piperazinas/síntesis química , Aminación , Ciclización , Modelos Moleculares , Conformación Molecular , Oxidación-Reducción
15.
Org Lett ; 6(17): 2885-8, 2004 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-15330639

RESUMEN

A mild method for the synthesis of carbamates from amino alcohols involves sequential carboxylation with carbon dioxide, followed by a Mitsunobu reaction. Unexpectedly, the stereochemical course of the Mitsunobu reaction is dependent on whether the carbamic acid intermediate is N-substituted with hydrogen (retention) or carbon (inversion).

16.
Angew Chem Int Ed Engl ; 37(19): 2704-2708, 1998 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-29711602

RESUMEN

Controlling the elements of planar and axial chirality are the principal challenges in the synthesis of the aglycon of vancomycin. Vancomycin is the prototypical member of the glycopeptide family of antibiotics which are effective for the treatment of infections by methicillin-resistant Staphylococcus aureus. The first total syntheses of the vancomycin and eremomycin aglycons provide insight into the influence of structure on kinetic and thermodynamic control of atropselective macrocyclizations.

17.
J Med Chem ; 56(6): 2294-310, 2013 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-23379595

RESUMEN

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.


Asunto(s)
Benzocicloheptenos/metabolismo , Benzocicloheptenos/farmacología , Descubrimiento de Drogas , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Sulfonamidas/metabolismo , Sulfonamidas/farmacología , Animales , Benzocicloheptenos/química , Línea Celular Tumoral , Perros , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Ratones , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/química , Ratas , Especificidad por Sustrato , Sulfonamidas/química , Ensayos Antitumor por Modelo de Xenoinjerto
18.
J Med Chem ; 54(20): 7334-49, 2011 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-21942426

RESUMEN

The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.


Asunto(s)
Carbolinas/síntesis química , Indoles/síntesis química , Janus Quinasa 2/antagonistas & inhibidores , Trastornos Mieloproliferativos/tratamiento farmacológico , Piridinas/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Carbolinas/farmacocinética , Carbolinas/farmacología , Cristalografía por Rayos X , Perros , Haplorrinos , Hepatocitos/metabolismo , Indoles/farmacocinética , Indoles/farmacología , Janus Quinasa 2/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Fosforilación , Policitemia Vera/tratamiento farmacológico , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad
19.
J Med Chem ; 54(12): 4092-108, 2011 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-21608528

RESUMEN

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.


Asunto(s)
Antineoplásicos/síntesis química , Benzocicloheptenos/síntesis química , Piridinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzocicloheptenos/farmacocinética , Benzocicloheptenos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Haplorrinos , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Mutación , Trasplante de Neoplasias , Fosforilación , Unión Proteica , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirazoles/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Proteínas Tirosina Quinasas Receptoras/genética , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Trasplante Heterólogo
20.
Org Lett ; 12(6): 1340-3, 2010 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-20175533

RESUMEN

A mild and efficient library synthesis technique has been developed for the synthesis of ureas and carbamates from carbamic acids derived from the DBU-catalyzed reaction of amines and gaseous carbon dioxide. Carbamic acids derived from primary amines reacted with Mitsunobu reagents to generate isocyanates in situ which were condensed with primary and secondary amines to afford the desired ureas. Similarly, carbamic acids from secondary amines reacted with alcohols activated with Mitsunobu reagents to form carbamates.


Asunto(s)
Aminas/química , Carbamatos/síntesis química , Dióxido de Carbono/química , Urea/síntesis química , Carbamatos/química , Técnicas Químicas Combinatorias , Estructura Molecular , Urea/análogos & derivados , Urea/química
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