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1.
J Med Chem ; 62(15): 6876-6893, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31282155

RESUMEN

The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2α inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.


Asunto(s)
Antineoplásicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma de Células Renales/tratamiento farmacológico , Indanos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Sulfonas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinoma de Células Renales/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Femenino , Haplorrinos , Humanos , Indanos/síntesis química , Indanos/farmacología , Neoplasias Renales/metabolismo , Ratones , Ratones SCID , Ratas , Sulfonas/síntesis química , Sulfonas/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
2.
J Med Chem ; 61(21): 9691-9721, 2018 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-30289716

RESUMEN

HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*Ar interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC50 = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma de Células Renales/patología , Diseño de Fármacos , Indanos/química , Indanos/farmacología , Neoplasias Renales/patología , Sulfonas/química , Sulfonas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Línea Celular Tumoral , Perros , Indanos/farmacocinética , Ratones , Modelos Moleculares , Conformación Proteica , Ratas , Relación Estructura-Actividad , Sulfonas/farmacocinética , Distribución Tisular
3.
J Clin Oncol ; 36(9): 867-874, 2018 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-29257710

RESUMEN

Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma de Células Renales/tratamiento farmacológico , Indanos/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Sulfonas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indanos/efectos adversos , Indanos/sangre , Neoplasias Renales/sangre , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Sulfonas/efectos adversos , Sulfonas/sangre
4.
Nature ; 539(7627): 107-111, 2016 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-27595393

RESUMEN

Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Indanos/farmacología , Indanos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Sulfonas/farmacología , Sulfonas/uso terapéutico , Animales , Biomarcadores Farmacológicos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ratones , Modelos Biológicos , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Transcripción Genética/efectos de los fármacos , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Nature ; 539(7627): 112-117, 2016 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-27595394

RESUMEN

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Indanos/farmacología , Indanos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Sulfonas/farmacología , Sulfonas/uso terapéutico , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Sitios de Unión , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Transformación Celular Neoplásica , Resistencia a Antineoplásicos/efectos de los fármacos , Eritropoyetina/antagonistas & inhibidores , Eritropoyetina/sangre , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Indanos/administración & dosificación , Indoles/farmacología , Indoles/uso terapéutico , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Terapia Molecular Dirigida , Mutación , Pirroles/farmacología , Pirroles/uso terapéutico , Reproducibilidad de los Resultados , Sulfonas/administración & dosificación , Sunitinib , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Cancer Res ; 76(18): 5491-500, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27635045

RESUMEN

More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1ß. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR.


Asunto(s)
Antineoplásicos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Animales , Antineoplásicos/química , Calorimetría , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Inmunohistoquímica , Inmunoprecipitación , Ratones , Ratones SCID , Reacción en Cadena de la Polimerasa , Ensayos Antitumor por Modelo de Xenoinjerto
7.
J Med Chem ; 57(5): 1753-69, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-23672640

RESUMEN

HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.


Asunto(s)
Antivirales/uso terapéutico , Descubrimiento de Drogas , Lactamas/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Sulfonamidas/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacología , Cristalografía por Rayos X , Ciclopropanos , Perros , Isoindoles , Lactamas/química , Lactamas/farmacología , Lactamas Macrocíclicas , Macaca fascicularis , Estructura Molecular , Prolina/análogos & derivados , Inhibidores de Proteasas/farmacología , Ratas , Sulfonamidas/química , Sulfonamidas/farmacología
8.
ACS Med Chem Lett ; 3(9): 705-9, 2012 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-24900538

RESUMEN

Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.

9.
J Med Chem ; 54(8): 2839-63, 2011 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-21417219

RESUMEN

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.


Asunto(s)
Ciclopropanos/química , Ciclopropanos/farmacología , Descubrimiento de Drogas , Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Animales , Cristalografía por Rayos X , Ciclopropanos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Ratones Noqueados , Modelos Moleculares , Relación Estructura-Actividad
11.
Bioorg Med Chem Lett ; 19(13): 3637-41, 2009 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-19447623

RESUMEN

The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.


Asunto(s)
Antivirales/síntesis química , Benzotiadiazinas/síntesis química , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hepacivirus/efectos de los fármacos , Tiazinas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Antivirales/farmacología , Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Biología Computacional , Simulación por Computador , Cristalografía por Rayos X , ARN Polimerasas Dirigidas por ADN/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Unión Proteica , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacología , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacos
14.
Antimicrob Agents Chemother ; 52(12): 4432-41, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18824605

RESUMEN

Future treatments for chronic hepatitis C virus (HCV) infection are likely to include agents that target viral components directly. Here, the preclinical characteristics of ITMN-191, a peptidomimetic inhibitor of the NS3/4A protease of HCV, are described. ITMN-191 inhibited a reference genotype 1 NS3/4A protein in a time-dependent fashion, a hallmark of an inhibitor with a two-step binding mechanism and a low dissociation rate. Under preequilibrium conditions, 290 pM ITMN-191 half-maximally inhibited the reference NS3/4A protease, but a 35,000-fold-higher concentration did not appreciably inhibit a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Subnanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 4, 5, and 6, while single-digit nanomolar potency was observed against NS3/4A from genotypes 2b and 3a. Dilution of a preformed enzyme inhibitor complex indicated ITMN-191 remained bound to and inhibited NS3/4A for more than 5 h after its initial association. In cell-based potency assays, half-maximal reduction of genotype 1b HCV replicon RNA was afforded by 1.8 nM; 45 nM eliminated the HCV replicon from cells. Peginterferon alfa-2a displayed a significant degree of antiviral synergy with ITMN-191 and reduced the concentration of ITMN-191 required for HCV replicon elimination. A 30-mg/kg of body weight oral dose administered to rats or monkeys yielded liver concentrations 12 h after dosing that exceeded the ITMN-191 concentration required to eliminate replicon RNA from cells. These preclinical characteristics compare favorably to those of other inhibitors of NS3/4A in clinical development and therefore support the clinical investigation of ITMN-191 for the treatment of chronic hepatitis C.


Asunto(s)
Antivirales , Proteínas Portadoras/antagonistas & inhibidores , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Inhibidores de Proteasas , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/metabolismo , Antivirales/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Hepacivirus/genética , Hepacivirus/fisiología , Humanos , Interferón alfa-2 , Interferón-alfa/farmacología , Péptidos y Proteínas de Señalización Intracelular , Hígado/metabolismo , Macaca fascicularis , Polietilenglicoles/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Ratas , Proteínas Recombinantes , Replicación Viral/efectos de los fármacos
15.
J Med Chem ; 51(15): 4672-84, 2008 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-18646745

RESUMEN

The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.


Asunto(s)
Aminas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor trkA/antagonistas & inhibidores , Animales , Línea Celular , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Ratas Wistar , Receptor trkA/química , Receptor trkA/metabolismo , Relación Estructura-Actividad
16.
J Comb Chem ; 9(6): 1177-87, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17824665

RESUMEN

Due to their diverse range of biological activities, imidazoheterocycles are recognized as privileged structures making these structural motifs attractive targets for library preparation. We report herein the synthesis of a sizable collection of imidazo[1,2- a]heterocycle scaffolds well-suited for divergent library preparation by virtue of amine functional handles with diverse positioning and connectivities. Partial reduction of imidazo[1,2- a]pyrazines to the tetrahydroimidazo[1,2- a]pyrazines and regiospecific Mannich-type bond formation at the C-3 of imidazo[1,2- a]pyridine under mild conditions achieved additional topological and connective diversity within the scaffold collection. Subsequent parallel reaction of the functionalized imidazoheterocycles with polystyrene-tetrafluorophenol esters and sulfonates produced a 7500 compound library in high purity.


Asunto(s)
Aldehídos/química , Aminas/química , Técnicas Químicas Combinatorias , Compuestos Heterocíclicos/síntesis química , Imidazoles/síntesis química , Nitrilos/química , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Ésteres/química , Modelos Químicos , Fenoles/química , Poliestirenos/química , Piridinas/química , Ácidos Sulfónicos/química
17.
Org Lett ; 5(15): 2727-30, 2003 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-12868900

RESUMEN

[reaction: see text] The bicyclocondensation of 3-aza-1,5-ketoacids and amino alcohols furnished novel oxazolo[3,2-a]pyrazin-5-one scaffolds possessing angular, ring junction substituents in high yield with excellent levels of substrate-based diastereocontrol. Mild oxidation of serinol-derived scaffolds provided access to a new class of constrained dipeptide surrogates. Deprotection of the endocyclic amine contained within these scaffolds allows for further diversification via N-functionalization.


Asunto(s)
Amino Alcoholes/química , Compuestos Aza/química , Cetoácidos/química , Cetonas/síntesis química , Lactamas/química , Oxazoles/síntesis química , Pirazinas/síntesis química , Ciclización , Oxidación-Reducción , Propanolaminas , Glicoles de Propileno/química , Estereoisomerismo
18.
Org Lett ; 4(7): 1167-70, 2002 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-11922809

RESUMEN

[reaction: see text] The preparation and synthetic applications of a novel resin-bound isonitrile are described. The resin is an example of a novel convertible isonitrile that can be utilized in the Ugi multicomponent reaction. Base-activation of the resin-bound Ugi product results in cleavage via formation of a N-acyloxazolidone that is then trapped as a carboxylic acid ester. This resin and the methodology described are suitable for synthesizing diversity libraries of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones.


Asunto(s)
Benzodiazepinas/síntesis química , Nitrilos/química , Piperazinas/síntesis química , Cromatografía Líquida de Alta Presión , Indicadores y Reactivos , Espectrometría de Masas , Polímeros , Espectrofotometría Ultravioleta
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