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1.
Chembiochem ; 22(10): 1769-1774, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33491295

RESUMO

Herein, we report a general and simplified synthesis of fluorophosphonates directly from p-nitrophenylphosphonates. This FP on-demand reaction is mediated by a commercially available polymer-supported fluoride reagent that produces a variety (25 examples) of fluorophosphonates in high yields while only requiring reagent filtration for pure fluorophosphonate isolation. This reaction protocol facilitates the rapid profiling of serine hydrolases with diverse and novel sets of activated phosphonates with differential proteome reactivity. Moreover, slight modification of the procedure into a reaction-to-assay format has enabled additional screening efficiency.


Assuntos
Flúor/química , Organofosfonatos/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Humanos , Organofosfonatos/síntese química , Organofosfonatos/química , Polímeros/química , Serina Endopeptidases/metabolismo , Técnicas de Síntese em Fase Sólida
2.
J Med Chem ; 67(13): 10831-10847, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38888621

RESUMO

Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.


Assuntos
Encéfalo , Desenho de Fármacos , Receptor Muscarínico M4 , Receptor Muscarínico M4/metabolismo , Receptor Muscarínico M4/agonistas , Regulação Alostérica/efeitos dos fármacos , Humanos , Animais , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Relação Estrutura-Atividade , Ratos , Cricetulus , Células CHO , Agonistas Muscarínicos/farmacologia , Agonistas Muscarínicos/síntese química , Agonistas Muscarínicos/química , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
3.
Science ; 384(6694): eadk5864, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38662832

RESUMO

Chemical modulation of proteins enables a mechanistic understanding of biology and represents the foundation of most therapeutics. However, despite decades of research, 80% of the human proteome lacks functional ligands. Chemical proteomics has advanced fragment-based ligand discovery toward cellular systems, but throughput limitations have stymied the scalable identification of fragment-protein interactions. We report proteome-wide maps of protein-binding propensity for 407 structurally diverse small-molecule fragments. We verified that identified interactions can be advanced to active chemical probes of E3 ubiquitin ligases, transporters, and kinases. Integrating machine learning binary classifiers further enabled interpretable predictions of fragment behavior in cells. The resulting resource of fragment-protein interactions and predictive models will help to elucidate principles of molecular recognition and expedite ligand discovery efforts for hitherto undrugged proteins.


Assuntos
Descoberta de Drogas , Aprendizado de Máquina , Proteômica , Bibliotecas de Moléculas Pequenas , Humanos , Ligantes , Ligação Proteica , Proteoma/metabolismo , Proteômica/métodos , Bibliotecas de Moléculas Pequenas/química , Ubiquitina-Proteína Ligases/metabolismo
4.
J Org Chem ; 78(6): 2661-9, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23438191

RESUMO

A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey-Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation.


Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/química , Compostos Aza/síntese química , Metanol/química , Piperidinas/síntese química , Compostos de Espiro/síntese química , Compostos Aza/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Piperidinas/química , Inibidores de Proteases , Compostos de Espiro/química , Estereoisomerismo , Relação Estrutura-Atividade
5.
J Med Chem ; 66(5): 3195-3211, 2023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36802610

RESUMO

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.


Assuntos
Apetite , Receptor Tipo 4 de Melanocortina , Ratos , Humanos , Animais , Caquexia/tratamento farmacológico , Anorexia/tratamento farmacológico , Conformação Molecular
6.
ACS Med Chem Lett ; 12(10): 1585-1588, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34676040

RESUMO

The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.

7.
Science ; 374(6575): 1586-1593, 2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34726479

RESUMO

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.


Assuntos
Tratamento Farmacológico da COVID-19 , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/farmacologia , Leucina/uso terapêutico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/farmacologia , Prolina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêutico , Administração Oral , Animais , COVID-19/virologia , Ensaios Clínicos Fase I como Assunto , Coronavirus/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Lactamas/administração & dosagem , Lactamas/farmacocinética , Leucina/administração & dosagem , Leucina/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Prolina/administração & dosagem , Prolina/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , SARS-CoV-2/fisiologia , Inibidores de Protease Viral/administração & dosagem , Inibidores de Protease Viral/farmacocinética , Replicação Viral/efeitos dos fármacos
8.
Nat Commun ; 12(1): 6055, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663813

RESUMO

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.


Assuntos
Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/administração & dosagem , Indóis/administração & dosagem , Leucina/administração & dosagem , Pirrolidinonas/administração & dosagem , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacocinética , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/farmacocinética , Animais , COVID-19/virologia , Chlorocebus aethiops , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano 229E/enzimologia , Inibidores de Protease de Coronavírus/efeitos adversos , Inibidores de Protease de Coronavírus/farmacocinética , Modelos Animais de Doenças , Desenho de Fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células HeLa , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Infusões Intravenosas , Leucina/efeitos adversos , Leucina/farmacocinética , Camundongos , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/enzimologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Células Vero
9.
bioRxiv ; 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32935104

RESUMO

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.

10.
J Med Chem ; 61(10): 4476-4504, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29613789

RESUMO

A major challenge in the development of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/metabolismo , Desenho de Fármacos , Hipopigmentação , Inibidores de Proteases , Piranos , Pigmentação da Pele/efeitos dos fármacos , Tiazinas , Tiazóis , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Células Cultivadas , Cães , Humanos , Hipopigmentação/induzido quimicamente , Masculino , Melanócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/química , Conformação Proteica , Piranos/administração & dosagem , Piranos/efeitos adversos , Piranos/química , Tiazinas/administração & dosagem , Tiazinas/efeitos adversos , Tiazinas/química , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/química
11.
J Med Chem ; 60(1): 386-402, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-27997172

RESUMO

A growing subset of ß-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Anilidas/química , Inibidores Enzimáticos/farmacologia , Glicina/química , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide/química , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Cristalização , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Masculino , Camundongos , Técnicas de Patch-Clamp , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem
12.
J Med Chem ; 58(6): 2678-702, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25695670

RESUMO

The identification of centrally efficacious ß-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid ß (Aß) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aß-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.


Assuntos
Amidinas/química , Amidinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Placa Amiloide/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Amidinas/farmacocinética , Amidinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Cães , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos , Modelos Moleculares , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Ratos , Ratos Wistar , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacocinética , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/uso terapêutico
13.
J Med Chem ; 58(7): 3223-52, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25781223

RESUMO

In recent years, the first generation of ß-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/química , Citocromo P-450 CYP2D6/química , Interações Medicamentosas , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sequência de Aminoácidos , Proteínas Amiloidogênicas/metabolismo , Animais , Cristalografia por Raios X , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Concentração Inibidora 50 , Masculino , Camundongos Endogâmicos , Modelos Moleculares , Dados de Sequência Molecular , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/farmacocinética , Pirazóis/química , Relação Estrutura-Atividade
14.
J Med Chem ; 55(21): 9224-39, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-22984865

RESUMO

ß-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central Aß(X-40) levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of Aß lowering versus that observed in wild-type (WT) mouse at an equivalent dose.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Aza/síntese química , Encéfalo/metabolismo , Compostos de Espiro/síntese química , Sulfonamidas/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Cristalografia por Raios X , Cães , Desenho de Fármacos , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Permeabilidade , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Transfecção
15.
Org Lett ; 12(10): 2198-201, 2010 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-20397661

RESUMO

A general and efficient directed ortho metalation (DoM)-halogen dance (HD)-electrophile quench sequence for the synthesis of trisubstituted pyridyl O-carbamates is described. A second HD sequence furnishes highly functionalized tetrasubstituted pyridines. Furthermore, a hitherto unobserved double HD rearrangement is reported. Under similar LDA conditions, aromatic O-carbamates with OMe, Cl, and F substituents (4a-c) undergo either a HD-electrophile quench sequence, 4a-c --> 18-20, or a HD-anionic ortho Fries rearrangement, 4a-c --> 6a-c, respectively.


Assuntos
Carbamatos/síntese química , Carbamatos/química , Estrutura Molecular , Estereoisomerismo
16.
J Org Chem ; 72(5): 1588-94, 2007 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-17284076

RESUMO

A general method for the synthesis of azabiaryls 19a-t by a one-pot procedure involving a Directed ortho metalation (DoM)-boronation-Suzuki-Miyaura cross coupling sequence is described. Aside from the three isomeric pyridyl carboxamides 15a-c, chloro-, fluoro-, and O-carbamoyl pyridines are adapted to this method providing a range of azabiaryls (Table 2). The method has an advantage in that it avoids the recognized difficult isolation of pyridyl boronic acids and their instability toward deboronation. The efficient synthesis of hydroxypicolinamides 12-14 (Scheme 3) by a one-pot metalation-boronation-oxidation sequence with the LDA-B(OiPr)3 in situ procedure that avoids self-condensation of incipient ortho-metalated species (Scheme 2) is delineated. The conversion of azabiaryls 19b,e,h,l into azafluorenones 20b,e,h,l by a directed remote metalation protocol is demonstrated (Table 3). A comprehensive survey of pyridyl boronates, of considerable interest in contemporary heterocyclic synthetic chemistry, is given (Figure 1).


Assuntos
Compostos Aza/síntese química , Compostos de Boro/síntese química , Metais/química , Piridinas/síntese química , Boro/química , Cromatografia em Camada Fina , Indicadores e Reagentes , Lítio/química , Espectroscopia de Ressonância Magnética , Oxirredução
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