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1.
J Labelled Comp Radiopharm ; 62(11): 690-694, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31034626

RESUMO

The International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development recently established a working group focused on the development of a guidance to address Deuterated Active Pharmaceutical Ingredients. Deuteration of an Active Pharmaceutical Ingredient (API) in some cases can retard and/or alter API metabolism by exploiting the primary kinetic isotope effect. Several deuterated APIs have entered into the clinic, and one has recently been approved. In most cases, it is very difficult to nearly impossible to synthesize a 100% isotopically pure compound. This raises synthetic, analytical, and regulatory questions that warrant a science-based assessment and recommendations for synthetic methods, analytical methods, and specifications. A cross functional team of scientists with expertise in isotope chemistry, process chemistry, analytical chemistry, and drug metabolism and pharmacokinetics have been meeting under the auspices of IQ to define and address these questions. This paper strives to frame chemistry, manufacturing, and controls challenges.

2.
Artigo em Inglês | MEDLINE | ID: mdl-30156329

RESUMO

The isotopic labeling of molecules for agrichemical and pharmaceutical uses is becoming more challenging as molecules become larger, involve more stereochemistry, and as intellectual property rights become more complex. As such, isotope chemists need to continually add new isotopic methods to their armamentarium to successfully label complex molecules with carbon-13 and carbon-14. Recently, there has been a surge in the use of radicals to form new carbon-carbon bonds and for the incorporation of functional groups which can be used to incorporate isotopically labeled carbons. This review will describe some potential new radical methods for incorporating isotopically labeled carbon into complex molecules or into substrates that can be attached to late stage intermediates to generate labeled products.

3.
J Labelled Comp Radiopharm ; 60(8): 357-365, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28273377

RESUMO

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-816336 as an inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14 labeled material was required for use in metabolic profiling. [Phenyl-14 C(U)]BMS-816336 was synthesized in 8 steps and 22% radiochemical yield from commercially available [14 C(U)]bromobenzene. The radiochemical purity of [phenyl-14 C(U)]BMS-816336 was 100% having a specific activity of 84.4 µCi/mg or 28.8 mCi/mmol for a total of 8.9 mCi. It was also necessary to synthesize [13 C6 ]BMS-816336 for use as a liquid chromatography/mass spectrometry standard. [13 C6 ]BMS-816336 was also prepared in 8 labeled steps in 26% yield from [13 C6 ]bromobenzene.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Azetidinas/síntese química , Azetidinas/farmacologia , Isótopos de Carbono/química , Radioisótopos de Carbono/química , Diabetes Mellitus Tipo 2/enzimologia , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Azetidinas/química , Técnicas de Química Sintética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia
4.
J Labelled Comp Radiopharm ; 60(8): 352-356, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28273378

RESUMO

PEGylation is a proven approach to prolonging the duration of action and enhancing biophysical solubility and stability of peptides. 4-Acetylphenylalanine is a novel amino acid with a ketone side chain that is uniquely reactive in proteins. The ketone functionality can react with an aminooxy functionalized polyethyleneglycol polymer to form a stable oxime adduct of the protein. One concern with using unnatural amino acids, such as 4-acetylphenylalanine, is the possibility of it being cleaved from the peptide and becoming incorporated into endogenous proteins. To determine whether this occurs, an in vitro experiment to assess the cell viability and amino acid incorporation into endogenous proteins using primary male rat hepatocytes in the presence of [14 C]4-acetylphenylalanine, 4 or [14 C(U)]L-phenylalanine was conducted. [14 C]4-acetylphenylalanine, 4 was prepared in 2 radiochemical steps from [1-14 C]acetyl chloride in an overall 8% radiochemical yield and in 99.9% radiochemical purity. The results showed that there was no evidence of carbon-14 incorporation into hepatocyte endogenous proteins with [14 C]pAcF and there was no difference between it and L-phenylalanine in cell viability assessments at any of the concentrations studied between 0.1 and 1000 µM.


Assuntos
Radioisótopos de Carbono/química , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Fenilalanina/análogos & derivados , Proteínas/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo , Masculino , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Ratos , Ratos Sprague-Dawley
5.
Sci Transl Med ; 9(371)2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28053157

RESUMO

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.


Assuntos
Anticorpos/uso terapêutico , Fibrinolíticos/uso terapêutico , Hemorragia/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Receptores de Trombina/antagonistas & inibidores , Administração Oral , Animais , Plaquetas/metabolismo , Cobaias , Células HEK293 , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Domínios Proteicos , Receptor PAR-1/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Trombina/química , Trombose , Resultado do Tratamento
6.
J Med Chem ; 60(4): 1417-1431, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112924

RESUMO

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.


Assuntos
Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Receptores Acoplados a Proteínas-G/metabolismo
7.
J Labelled Comp Radiopharm ; 60(1): 49-54, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27966233

RESUMO

Tetrazoles are a common heterocyclic functionality in many biologically active molecules. [1-14 C]2-(1H-Tetrazol-5-yl)acetic acid was required as an intermediate in the synthesis of a development candidate as part of a discovery phase program to complete metabolic profiling studies. [1-14 C]2-(1H-Tetrazol-5-yl)acetic acid was prepared in 4 steps overall and in 3 radiochemical steps from K14 CN in an overall 32% radiochemical yield.


Assuntos
Acetatos/síntese química , Compostos Radiofarmacêuticos/síntese química , Tetrazóis/síntese química , Acetatos/química , Radioisótopos de Carbono/química , Compostos Radiofarmacêuticos/química , Tetrazóis/química
8.
J Labelled Comp Radiopharm ; 59(14): 665-672, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27624665

RESUMO

BMS-725519, BMS-811064, and BMS-812204 are potent and selective central cannabinoid receptor antagonists that have been investigated for the treatment of human obesity. To further understand their biotransformation profiles, radiolabelled and stable-labelled products were required. This paper describes the utility of [14 C]1,1-carbonyldiimidazole as a radiolabelling reagent for the syntheses of carbonyl-labelled [14 C]BMS-725519, [14 C]BMS-811064, and [14 C]BMS-812204. The syntheses of stable-labelled [13 C6 ]BMS-725519 and [13 CD313 CD2 ]BMS-812204 synthesized from of [13 C6 ]4-chloroacetophenone and [13 CD313 CD2 ]iodoethane, respectively, are also described.


Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/síntese química , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Isótopos de Carbono/química , Radioisótopos de Carbono/química , Técnicas de Química Sintética , Imidazóis/química , Marcação por Isótopo
9.
J Labelled Comp Radiopharm ; 59(14): 657-664, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27460954

RESUMO

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-770767 as an inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) for type 2 diabetes was required the synthesis of carbon-14-labelled material for use in metabolic profiling and for the human adsorption, distribution, metabolism and excretion (ADME) study. Initially, [phenyl-14 C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [14 C(U)]2-chlorophenol to give the desired final product in 18% yield. Later, the synthesis was completed for the human ADME clinical study using a combination of the discovery and process chemistry routes under cGMP to prepare [phenyl-14 C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl-14 C(U)]BMS-770767 after dilution with unlabelled clinical grade BMS-770767 was 99.1% having a specific activity of 1.61 µCi/mg. In addition, to support the quantification of BMS-770767 in LC/MS analyses, [13 C6 ]BMT-770767 was prepared in two steps from a late-stage intermediate and [13 C6 ]2-chlorophenol.


Assuntos
Absorção Fisico-Química , Radioisótopos de Carbono/química , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/síntese química , Piridinas/análise , Piridinas/síntese química , Triazóis/análise , Triazóis/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Biotransformação , Técnicas de Química Sintética , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Piridinas/metabolismo , Piridinas/farmacologia , Radioquímica , Triazóis/metabolismo , Triazóis/farmacologia
11.
J Labelled Comp Radiopharm ; 59(6): 255-9, 2016 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-27169762

RESUMO

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-823778 as an inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 for type 2 diabetes, the synthesis of carbon-14-labeled material was required for use in a human adsorption, distribution, metabolism, and excretion (ADME) study. The HCl salt form of [(14) C]BMS-823778 was synthesized in two steps from commercially available [2-(14) C]acetone. The radiochemical purity of the synthesized [(14) C]BMS-823778 after dilution with unlabeled clinical-grade BMS-823778 was 99.5% having a specific activity of 7.379 µCi/mg. One result of the human ADME study was the detection of a new human metabolite, BMT-094817. To support the quantification of BMT-094817 in clinical samples, it was necessary to synthesize [(13) CD3 (13) CD2 ]BMT-094817 for use as a liquid chromatography/mass spectrometry standard. [(13) CD3 (13) CD2 ]BMT-094817 was prepared in five labeled steps from [(13) CD3 ]iodomethane.


Assuntos
Radioisótopos de Carbono/química , Piridinas/síntese química , Piridinas/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Adsorção , Técnicas de Química Sintética , Humanos , Marcação por Isótopo , Piridinas/química , Triazóis/química
12.
Science ; 352(6287): 801-5, 2016 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-27103669

RESUMO

Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study demonstrates how the same activating principles used for decades to make simple C-N (amide) bonds from carboxylic acids with loss of water can be used to make C-C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).

14.
J Org Chem ; 80(14): 7019-32, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26151079

RESUMO

Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.


Assuntos
Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/metabolismo , Pró-Fármacos/síntese química , Ticlopidina/análogos & derivados , Fenômenos Biológicos , Clopidogrel , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Piperidinas/química , Inibidores da Agregação de Plaquetas/química , Pró-Fármacos/química , Estereoisomerismo , Ticlopidina/síntese química , Ticlopidina/química , Ticlopidina/metabolismo
15.
J Am Chem Soc ; 137(25): 8046-9, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26088401

RESUMO

A solution to the classic unsolved problem of olefin hydromethylation is presented. This highly chemoselective method can tolerate labile and reactive chemical functionalities and uses a simple set of reagents. An array of olefins, including mono-, di-, and trisubstituted olefins, are all smoothly hydromethylated. This mild protocol can be used to simplify the synthesis of a specific target or to directly "edit" complex natural products and other advanced materials. The method is also amenable to the simple installation of radioactive and stable labeled methyl groups.


Assuntos
Alcenos/química , Metano/química , Catálise , Metilação , Modelos Moleculares , Estereoisomerismo
16.
J Labelled Comp Radiopharm ; 57(12): 667-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25303408

RESUMO

Carbon-14 labeled linker molecule, N-succinimidyl-3-maleimidopropionate was prepared for disposition studies of PEGylated biologics. Our new route started with 100 mCi of carbon-14 labeled Potassium cyanide (KCN) to prepare 55 mCi of [1-(14)C]N-succinimidyl-3-maleimidopropionate, 6 in five steps. This represents a multiple of 5.5× improvement in the yield of the desired labeled product compared with our previous synthesis.


Assuntos
Maleimidas/síntese química , Compostos Radiofarmacêuticos/síntese química , Succinimidas/síntese química , Radioisótopos de Carbono/química , Maleimidas/química , Polietilenoglicóis/química , Compostos Radiofarmacêuticos/química , Succinimidas/química
17.
J Med Chem ; 57(18): 7509-22, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25165888

RESUMO

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).


Assuntos
Fármacos Antiobesidade/farmacologia , Descoberta de Drogas , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Masculino , Ratos
18.
J Labelled Comp Radiopharm ; 57(3): 136-40, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24519575

RESUMO

(14)C-labeled saxagliptin, (13) CD2-labeled saxagliptin, and its (13) CD2-labeled 5-hydroxy metabolite were synthesized to further support development of the compound for biological studies. This paper describes new syntheses leading to the desired compounds. A total of 3.0 mCi of (14)C-labeled saxagliptin was obtained with a specific activity of 53.98 µCi/mg (17.13 mCi/mmol). The radiochemical purity determined by HPLC was 99.29%, and the overall radiochemical yield was 3.0% based upon 100 mCi of [(14)C]CH2 I2 starting material. By following similar synthetic routes, 580.0 mg of (13)CD2-labeled saxagliptin and 153.1 mg of (13)CD2-labeled 5-hydroxysaxagliptin metabolite were prepared.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/química , Dipeptídeos/síntese química , Adamantano/síntese química , Adamantano/química , Adamantano/metabolismo , Isótopos de Carbono/química , Radioisótopos de Carbono/química , Técnicas de Química Sintética , Dipeptídeos/metabolismo
19.
J Labelled Comp Radiopharm ; 56(9-10): 492-4, 2013 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24285527

RESUMO

Adnectins™ are novel fibronectin-based proteins containing domains engineered to bind to targets of therapeutic interest. The molecular weights of adnectins are less than conventional monoclonal antibodies but larger than traditional small molecules. Until now, there has been no information on the placental transfer of adnectins. To assess placental permeability to adnectins in pregnant guinea pigs, a radiolabeled adnectin, ATI-1072, bound to polyethylene glycol through a [(14) C]Maleimide linker, was synthesized from [1,4-(14) C]Maleic acid. This publication describes the synthesis and analysis of PEG-[(14) C]Maleimide-adnectin ([(14) C]ATI-1072).


Assuntos
Fibronectinas/síntese química , Fibronectinas/metabolismo , Placenta/metabolismo , Polietilenoglicóis/química , Sequência de Aminoácidos , Animais , Radioisótopos de Carbono , Técnicas de Química Sintética , Feminino , Fibronectinas/química , Cobaias , Maleimidas/química , Gravidez
20.
Drug Metab Dispos ; 38(3): 448-58, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19940026

RESUMO

Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC(50) values >20 microM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 muM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f(m CYP) <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low.


Assuntos
Anticoagulantes/farmacocinética , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores do Fator Xa , Pirazóis/farmacocinética , Piridonas/farmacocinética , Envelhecimento , Células Cultivadas , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Avaliação Pré-Clínica de Medicamentos , Interações de Medicamentos , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Hidroxilação , Isoenzimas/administração & dosagem , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Cinética , Desentoxicação Metabólica Fase I , Microssomos/enzimologia , Microssomos/metabolismo , Especificidade de Órgãos , RNA Mensageiro/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/metabolismo
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