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1.
Nature ; 550(7677): 481-486, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29045389

RESUMO

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.


Assuntos
Piperidinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Animais , Apoenzimas/antagonistas & inibidores , Apoenzimas/química , Apoenzimas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Humanos , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Piperidinas/síntese química , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirazóis/síntese química , Pirimidinas/síntese química , Especificidade por Substrato , Transcrição Gênica/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Peptidase 7 Específica de Ubiquitina/química , Peptidase 7 Específica de Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem Lett ; 27(4): 1062-1069, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28131713

RESUMO

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.


Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Piridinas/farmacologia , Descoberta de Drogas , Humanos , Piridinas/farmacocinética , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 26(7): 1803-8, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26927423

RESUMO

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.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridonas/química , Piridonas/farmacologia , Benzimidazóis/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Janus Quinase 1/metabolismo , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Piridonas/síntese química , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 24(6): 1466-71, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24582987

RESUMO

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.


Assuntos
Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridonas/química , Sulfonamidas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Janus Quinase 2/metabolismo , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridonas/síntese química , Piridonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
5.
Elife ; 102021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34636321

RESUMO

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.


Assuntos
Proteínas de Ligação a DNA/genética , Deleção de Genes , Neoplasias Pulmonares/genética , Neoplasias de Células Escamosas/genética , Fatores de Transcrição/genética , Ubiquitina Tiolesterase/genética , Animais , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Fatores de Transcrição/metabolismo , Ubiquitina Tiolesterase/metabolismo
8.
J Med Chem ; 63(4): 1612-1623, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31971798

RESUMO

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.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Quinolinas/uso terapêutico , Quinolonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Quinolinas/síntese química , Quinolinas/metabolismo , Quinolonas/síntese química , Quinolonas/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Org Chem ; 74(22): 8866-9, 2009 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-19845317

RESUMO

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.


Assuntos
Boratos/química , Éteres/síntese química , Cetonas/síntese química , Paládio/química , Éteres/química , Cetonas/química , Estrutura Molecular , Sais/química , Estereoisomerismo
10.
J Pharmacol Exp Ther ; 324(1): 322-30, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17967939

RESUMO

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.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Isoquinolinas/uso terapêutico , Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/uso terapêutico , Piridinas/uso terapêutico , Animais , Fibrilação Atrial/fisiopatologia , Benzopiranos/uso terapêutico , Linhagem Celular , Cães , Feminino , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Humanos , Masculino , Piperidinas/uso terapêutico , Propafenona/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico
11.
J Med Chem ; 60(23): 9676-9690, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29156136

RESUMO

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.


Assuntos
Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Animais , Cães , Descoberta de Drogas , Halogenação , Humanos , Janus Quinase 1/química , Janus Quinase 1/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Ratos , Relação Estrutura-Atividade
12.
J Med Chem ; 49(24): 6954-7, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125248

RESUMO

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.


Assuntos
Antiarrítmicos/síntese química , Fibrilação Atrial/tratamento farmacológico , Isoquinolinas/síntese química , Canal de Potássio Kv1.5/antagonistas & inibidores , Nitrilas/síntese química , Administração Oral , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Disponibilidade Biológica , Eletrofisiologia , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Canal de Potássio Kv1.5/fisiologia , Nitrilas/química , Nitrilas/farmacologia , Técnicas de Patch-Clamp , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
13.
Curr Top Med Chem ; 3(10): 1075-93, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12769709

RESUMO

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.


Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/química , Inibidores Enzimáticos/química , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Farnesiltranstransferase , Humanos , Estrutura Molecular , Neoplasias/enzimologia , Prenilação de Proteína , Relação Estrutura-Atividade
14.
Org Lett ; 4(7): 1201-4, 2002 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-11922818

RESUMO

[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.


Assuntos
Piperazinas/síntese química , Aminação , Ciclização , Modelos Moleculares , Conformação Molecular , Oxirredução
15.
Org Lett ; 6(17): 2885-8, 2004 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-15330639

RESUMO

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.
Artigo em Inglês | MEDLINE | ID: mdl-29711602

RESUMO

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.
Artigo em Inglês | MEDLINE | ID: mdl-23379595

RESUMO

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.


Assuntos
Benzocicloeptenos/metabolismo , Benzocicloeptenos/farmacologia , Descoberta de Drogas , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Animais , Benzocicloeptenos/química , Linhagem Celular Tumoral , Cães , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Camundongos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/química , Ratos , Especificidade por Substrato , Sulfonamidas/química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Med Chem ; 54(20): 7334-49, 2011 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-21942426

RESUMO

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.


Assuntos
Carbolinas/síntese química , Indóis/síntese química , Janus Quinase 2/antagonistas & inibidores , Transtornos Mieloproliferativos/tratamento farmacológico , Piridinas/síntese química , Pirimidinas/síntese química , Administração Oral , Animais , Carbolinas/farmacocinética , Carbolinas/farmacologia , Cristalografia por Raios X , Cães , Haplorrinos , Hepatócitos/metabolismo , Indóis/farmacocinética , Indóis/farmacologia , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Fosforilação , Policitemia Vera/tratamento farmacológico , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
19.
J Med Chem ; 54(12): 4092-108, 2011 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-21608528

RESUMO

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.


Assuntos
Antineoplásicos/síntese química , Benzocicloeptenos/síntese química , Piridinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzocicloeptenos/farmacocinética , Benzocicloeptenos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Haplorrinos , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Mutação , Transplante de Neoplasias , Fosforilação , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptores Proteína Tirosina Quinases/genética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Transplante Heterólogo
20.
Org Lett ; 12(6): 1340-3, 2010 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-20175533

RESUMO

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.


Assuntos
Aminas/química , Carbamatos/síntese química , Dióxido de Carbono/química , Ureia/síntese química , Carbamatos/química , Técnicas de Química Combinatória , Estrutura Molecular , Ureia/análogos & derivados , Ureia/química
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