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1.
Anal Chem ; 92(8): 6051-6059, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32242660

RESUMO

Electrospray ionization (ESI) in-source fragmentation (ISF) has traditionally been minimized to promote precursor molecular ion formation, and therefore its value in molecular identification is underappreciated. In-source annotation algorithms have been shown to increase confidence in putative identifications by using ubiquitous in-source fragments. However, these in-source annotation algorithms are limited by ESI sources that are generally designed to minimize ISF. In this study, enhanced in-source fragmentation annotation (eISA) was created by tuning the ISF conditions to generate in-source fragmentation patterns comparable with higher energy fragments generated at higher collision energies as deposited in the METLIN MS/MS library, without compromising the intensity of precursor ions (median loss ≤10% in both positive and negative ionization modes). The analysis of 50 molecules was used to validate the approach in comparison to MS/MS spectra produced via data dependent acquisition (DDA) and data independent acquisition (DIA) mode with quadrupole time-of-flight mass spectrometry (QTOF-MS). Enhanced ISF as compared to QTOF DDA enabled higher peak intensities for the precursor ions (median: 18 times in negative mode and 210 times in positive mode), with the eISA fragmentation patterns consistent with METLIN for over 90% of the molecules with respect to fragment relative intensity and m/z. eISA also provides higher peak intensity as opposed to QTOF DIA for over 60% of the precursor ions in negative mode (median increase: 20%) and for 88% of the precursor ions in positive mode (median increase: 80%). Molecular identification with eISA was also successfully validated from the analysis of a metabolic extract from macrophages. An interesting side benefit of enhanced ISF is that it significantly improved molecular identification confidence with low resolution single quadrupole mass-spectrometry-based untargeted LC/MS experiments. Overall, enhanced ISF allowed for eISA to be used as a more sensitive alternative to other QTOF DIA and DDA approaches, and further, it enabled the acquisition of ESI TOF and ESI single quadrupole mass spectrometry instrumentation spectra with improved molecular identification confidence.


Assuntos
Compostos Orgânicos/análise , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
2.
Bioorg Med Chem Lett ; 20(14): 4027-31, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20610151

RESUMO

A novel family of 1H-imidazol-2-yl-pyrimidine-4,6-diamines has been identified with potent activity against the erythrocyte-stage of Plasmodium falciparum (Pf), the most common causative agent of malaria. A systematic SAR study resulted in the identification of compound 40 which exhibits good potency against both wild-type and drug resistant parasites and exhibits good in vivo pharmacokinetic properties.


Assuntos
Antimaláricos/química , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/química , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Descoberta de Drogas , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-Atividade
3.
J Pharm Sci ; 109(11): 3285-3291, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32745563

RESUMO

In vitro absorption, distribution, metabolism and elimination (ADME) assays are widely used for profiling compounds in pharmaceutical drug discovery programs. Many compounds are screened in metabolic stability assays, using liver microsomes as a model of intrinsic hepatic clearance. Analysis of metabolic stability assays has relied on high throughput LC-MS/MS techniques to keep up with automated assays and compound profiling needs. An experimental alternative to sample analysis via fast chromatography employs an open port interface (OPI) which dilutes and directs acoustically-ejected droplets from microtiter plates to a conventional electrospray ion source for ionization and introduction into a mass spectrometer. Metabolic stability assays of 37 commercial drug compounds using in human, dog, rat and mouse liver microsomes (LMs), were analyzed by LC-MS/MS and an experimental breadboard version of an ADE-OPI-MS/MS system. Results from the experiments comparing intrinsic clearance (CLint) generated with ADE-OPI-MS/MS vs fast LC-MS/MS for all compounds showed ≥86% of CLint values were within a factor of two with R2 ≥ 0.86 using 25 nL and 5 nL sample ejection volumes on the ADE-OPI-MS/MS instrument. Throughput with the experimental ADE-OPI-MS/MS system used in this study was more than ten-fold faster than analysis by the fast LC-MS/MS at 1.3 s/sample versus 17.2 s/sample, respectively.


Assuntos
Microssomos Hepáticos , Espectrometria de Massas em Tandem , Acústica , Animais , Cromatografia Líquida , Cães , Descoberta de Drogas , Camundongos , Ratos
4.
Bioorg Med Chem Lett ; 19(24): 6970-4, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19879133

RESUMO

Screening our in-house compound collection using a cell based Plasmodium falciparum proliferation assay we discovered a known pan-kinase inhibitor scaffold as a hit. Further optimization of this series led us to a novel benzamide scaffold which was devoid of human kinase activity while retaining its antiplasmodial activity. The evolution of this compound series leading to optimized candidates with good cellular potency against multiple strains as well as decent in vivo profile is described in this Letter.


Assuntos
Antimaláricos/química , Benzamidas/química , Inibidores Enzimáticos/química , Fosfotransferases/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Animais , Antimaláricos/síntese química , Antimaláricos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Evolução Molecular Direcionada , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Plasmodium falciparum/efeitos dos fármacos
5.
J Pharm Sci ; 108(2): 1053-1060, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30336155

RESUMO

Accurate determination of the free fraction of a drug in plasma can be challenging when it falls below 1% and even more so when below 0.1%. Equilibrium dialysis with diluted plasma has been used to determine unbound fraction below 1%, but some analytes are not amenable to this method. One robust alternative for accurately measuring very highly bound compounds is equilibrium gel filtration; however, radiolabeled compounds have been used with this technique to quantify the low analyte concentrations. This report examined results obtained using radiolabeled compounds with liquid scintillation detection and those obtained using their nonradiolabeled analogs with liquid chromatography-tandem mass spectrometry detection. The 2 methods provided comparable results over the range of 0.005%-4% free, with a slope of 1.0 and a R2 = 0.93. These results demonstrate that equilibrium gel filtration with liquid chromatography-tandem mass spectrometry detection can be used earlier in the drug discovery process to determine the unbound fraction of highly bound drugs and may help obviate the need for radiolabeled compound.


Assuntos
Proteínas Sanguíneas/metabolismo , Preparações Farmacêuticas/metabolismo , Cromatografia em Gel/métodos , Cromatografia Líquida/métodos , Humanos , Preparações Farmacêuticas/sangue , Ligação Proteica , Espectrometria de Massas em Tandem/métodos
6.
Drug Discov Today ; 13(7-8): 360-7, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18405850

RESUMO

Described in this article are strategies implemented to increase the throughput of in vivo rodent pharmacokinetic (PK) studies using the snapshot PK study design and automated methods for compound submission, sample processing, data analysis and reporting. Applying snapshot PK studies to categorize the oral exposure of >1300 discovery compounds as low, moderate or high resulted in an attrition rate of 86%. The follow up full PK studies on the remaining compounds found that 98% of the compounds were predicted in the correct (69%) or adjacent (29%) oral exposure category by the snapshot PK studies. These results demonstrate that the snapshot PK screen in rodents can serve as an effective and efficient in vivo tool in the compound selection process in drug discovery.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Preparações Farmacêuticas , Farmacocinética , Animais , Desenho de Fármacos , Camundongos , Ratos
7.
J Biomol Screen ; 11(3): 318-22, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16490775

RESUMO

The 1,536-well microplate format has widely supplanted the 384-well microplate format for high-throughput screening and for IC(50) assays. Previously, liquid chromatography/mass spectrometry (LC/MS) analyses of such samples required manual transfers of the wells of interest from a 1,536-well plate into a 384-well plate. Because this manual transfer introduced a source of potential error, it became clear that a more appropriate solution would be to sample directly from the 1,536-well plates. Currently, commercially available 1,536-well plate auto samplers are not compatible with Waters LC/MS systems. The authors have modified their CTC PAL autosampler to support injection from up to twenty-four 1,536-well plates. This allows them to cherry-pick any sample from up to 36,864 wells on the autosampler. Because of its success at this Institute, sampling from 1,536-well plates has not only become the preferred method for LC/MS analysis from IC(50) plates but also become the standard format used for the handling of and the sampling from large combinatorial libraries.


Assuntos
Cromatografia Líquida/instrumentação , Espectrofotometria Ultravioleta/instrumentação , Cromatografia Líquida/métodos , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta/métodos
8.
J Biomol Screen ; 11(8): 933-9, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17092919

RESUMO

Many companies possess a compound collection consisting of purified compounds and of unpurified products from combinatorial libraries. Using commercial and proprietary compounds as examples, this report provides clear examples of the significant impact purification can have on the activity observed for a compound and highlights the need to retest the purified compounds prior to creating structure-activity relationships. Crude mixtures made with commercial compounds led to an increase in the number of false positives in the SXR-GAL4 assay as compared with their pure and purified counterparts. An examination of proprietary compounds in an HIV assay resulted in the purification of 61 active crude synthetic mixtures. Of these 61 compounds, 32 were 5-fold less active and 2 were 5-fold more active after purification. This report details a semiautomated process developed and implemented for cherry-picking, tracking, and selectively purifying compounds found active in high-throughput screening campaigns.


Assuntos
Técnicas de Química Combinatória , Avaliação Pré-Clínica de Medicamentos/métodos , Cromatografia Líquida , Desenho de Fármacos , Reações Falso-Positivas , Espectrometria de Massas , Manejo de Espécimes
9.
J Med Chem ; 59(14): 6671-89, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27433829

RESUMO

Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Nicotina/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Conformação Molecular , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nicotina/síntese química , Nicotina/química , Nicotina/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
10.
J Chromatogr A ; 1092(2): 228-34, 2005 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-16199230

RESUMO

Following purification, the fractions of purified samples typically are analyzed to determine the relative purities of each fraction. We report a novel technique for performing post-purification analysis immediately after each preparative LC/MS run. The Single Pass Compound Purification and Analysis System (SPACPASS) samples and stores a representative aliquot from the fraction while it is being collected. Demonstrated for '1:1' fraction collections, this method of fraction purity assessment streamlined sample processing by reducing post-purification sample handling. For 97% of the collected fractions, this technique provided relative purities to within +/-5% when compared with more traditional post-purification analysis.


Assuntos
Cromatografia Líquida/métodos , Calibragem , Espectrofotometria Ultravioleta
11.
Geobiology ; 12(1): 99-108, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24325309

RESUMO

The Copper Harbor Conglomerate is a Mesoproterozoic (1.09 Ga) freshwater sedimentary sequence that outcrops in the Upper Peninsula of Michigan. The formation was deposited during infilling of the failed Midcontinent Rift and contains fluvial, lacustrine, and alluvial fan facies. This study describes and analyzes the formation of small domal structures preserved in fluvial sandstone facies within the lower portion of the formation. These domal structures range from millimeters to several centimeters in diameter and height, and are preserved in convex epirelief on fine-grained sandstone beds. The structures have a pustulose texture and a patchy distribution on bedding planes. Slabs containing the structures were collected in the field and analyzed in the laboratory through inspection of cut slabs, petrographic thin sections, X-radiographs, and RAMAN spectroscopy. Results of these analyses reveal that the domal structures often contain weak, wavy horizontal bedding and laminae, and lack any vertical structures. These results support a biogenic origin of the domal structures instead of through abiogenic processes such as loading, sand volcanoes, or adhesion warts. These structures are akin to what were traditionally labeled as 'sand stromatolites', but are now known as 'domal sand structures'. Along with previous descriptions of carbonate stromatolites, organic-rich paleosols, and microbial sand structures, our findings provide further evidence that mat-forming microbial communities thrived in the late Mesoproterozoic freshwater systems of the Midcontinent Rift.


Assuntos
Água Doce/microbiologia , Sedimentos Geológicos/microbiologia , Michigan
13.
Drug Discov Today ; 18(1-2): 71-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22982770

RESUMO

Successful drug discovery relies on the selection of drug candidates with good in vivo pharmacokinetic (PK) properties as well as appropriate preclinical efficacy and safety profiles. In vivo PK profiling is often a bottleneck in the discovery process. In this review, we focus on the tiered in vivo PK approaches implemented at the Genomics Institute of the Novartis Research Foundation (GNF), which includes snapshot PK, rapid PK and full PK studies. These in vivo PK approaches are well integrated within discovery research, allow tremendous flexibility and are highly efficient in supporting the diverse needs and increasing demand for in vivo profiling. The tiered in vivo PK studies expedite compound profiling and help guide the selection of more desirable compounds into efficacy models and for progression into development.


Assuntos
Desenho de Fármacos , Modelos Biológicos , Farmacocinética , Animais , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Preparações Farmacêuticas/metabolismo
14.
J Med Chem ; 55(9): 4244-73, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22524250

RESUMO

On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.


Assuntos
Antimaláricos/farmacologia , Imidazóis/farmacologia , Malária Falciparum/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Malária Falciparum/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Plasmodium falciparum/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade
15.
J Med Chem ; 54(14): 5116-30, 2011 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-21644570

RESUMO

Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.


Assuntos
Antimaláricos/síntese química , Imidazóis/síntese química , Piperazinas/síntese química , Aminoácidos/síntese química , Aminoácidos/química , Aminoácidos/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Linhagem Celular , Resistência a Medicamentos , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Malária/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Piperazinas/química , Piperazinas/farmacologia , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
16.
J Pharm Sci ; 99(11): 4463-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20845445

RESUMO

With the extensive use of different strains of mice and rats in in vivo efficacy models, lack of relevant metabolic clearance data among strains has been a concern. Metabolic clearance is an important parameter impacting drug discovery, and it is often used as a compound selection filter. Metabolically stable compounds are often preferred, and will have a better chance to achieve the desired exposure in vivo. The present study examined strain differences in mouse and rat, using 96 compounds which spanned a wide range of intrinsic clearances. The in vitro clearances were determined using liver microsomes from commonly used strains of mouse (BALB/c, C57BL/6J, and CD-1) and of rat (Sprague-Dawley, Fischer, and Wistar Han). There were few discrepancies in the interpretation of the in vitro intrinsic clearance results within species for the 96 compounds tested in mouse and rat liver microsomes. This data gives us confidence that the phase I hepatic clearance can be determined using only one strain of mouse or rat liver microsomes.


Assuntos
Descoberta de Drogas , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Descoberta de Drogas/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Wistar , Especificidade da Espécie
17.
Science ; 315(5808): 87-91, 2007 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-17204648

RESUMO

The late Paleozoic deglaciation is the vegetated Earth's only recorded icehouse-to-greenhouse transition, yet the climate dynamics remain enigmatic. By using the stable isotopic compositions of soil-formed minerals, fossil-plant matter, and shallow-water brachiopods, we estimated atmospheric partial pressure of carbon dioxide (pCO2) and tropical marine surface temperatures during this climate transition. Comparison to southern Gondwanan glacial records documents covariance between inferred shifts in pCO2, temperature, and ice volume consistent with greenhouse gas forcing of climate. Major restructuring of paleotropical flora in western Euramerica occurred in step with climate and pCO2 shifts, illustrating the biotic impact associated with past CO2-forced turnover to a permanent ice-free world.


Assuntos
Atmosfera , Dióxido de Carbono , Clima , Ecossistema , Plantas , Animais , Biodiversidade , Carbonato de Cálcio/análise , Isótopos de Carbono , Fósseis , Efeito Estufa , Camada de Gelo , Invertebrados/química , Estações do Ano , Solo/análise , Temperatura , Tempo
18.
J Comb Chem ; 7(2): 210-7, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15762748

RESUMO

In this paper we report using a parallel, four-channel HPLC/MUX/MS purification system, the Purification Factory, to purify thousands of compounds destined for high-throughput screening in a single month. The maximum sample throughput during this 20-workday month was 704 samples/day. Since this purification throughput exceeded the postpurification sample and data handling capabilities provided by commercial solutions, a custom-integrated solution was designed to address these shortcomings. In this paper we detail the key improvements in automation, solvent handling, and sample handling logistics implemented to sustain a mean throughput of 528 samples/day over a multimonth time period.


Assuntos
Técnicas de Química Combinatória/métodos , Preparações Farmacêuticas/isolamento & purificação , Autoanálise , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Espectrometria de Massas , Preparações Farmacêuticas/normas , Controle de Qualidade , Robótica
19.
Anal Chem ; 74(13): 3055-62, 2002 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12141664

RESUMO

We report on the development of a parallel HPLC/MS purification system incorporating an indexed (i.e., multiplexed) ion source. In the method described, each of the flow streams from a parallel array of HPLC columns is directed toward the multiplexed (MUX) ion source and sampled in a time-dependent, parallel manner. A visual basic application has been developed and monitors in real-time the extracted ion current from each sprayer channel. Mass-directed fraction collection is initiated into a parallel array of fraction collectors specific for each of the spray channels. In the first embodiment of this technique, we report on a four-column semipreparative parallel LC/MS system incorporating MUX detection. In this parallel LC/MS application (in which sample loads between 1 and 10 mg on-column are typically made), no cross talk was observed. Ion signals from each of the channels were found reproducible over 192 injections, with interchannel signal variations between 11 and 17%. The visual basic fraction collection application permits preset individual start collection and end collection thresholds for each channel, thereby compensating for the slight variation in signal between sprayers. By incorporating postfraction collector UV detection, we have been able to optimize the valve-triggering delay time with precut transfer tubing between the mass spectrometer and fraction collectors and achieve recoveries greater than 80%. Examples of the MUX-guided, mass-directed fraction purification of both standards and real library reaction mixtures are presented within.


Assuntos
Espectrometria de Massas/métodos , Cromatografia Líquida de Alta Pressão , Técnicas de Química Combinatória , Indicadores e Reagentes , Software , Espectrofotometria Ultravioleta
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