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1.
Nature ; 589(7843): 542-547, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33238289

RESUMO

Positron emission tomography (PET) radioligands (radioactively labelled tracer compounds) are extremely useful for in vivo characterization of central nervous system drug candidates, neurodegenerative diseases and numerous oncology targets1. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands2, yet there exist few radiolabelling protocols for the synthesis of either, inhibiting the development of PET radioligands. The synthesis of such radioligands also needs to be very rapid owing to the short half-life of carbon-11. Here we report a versatile and rapid metallaphotoredox-catalysed method for late-stage installation of both tritium and carbon-11 into the desired compounds via methylation of pharmaceutical precursors bearing aryl and alkyl bromides. Methyl groups are among the most prevalent structural elements found in bioactive molecules, and so this synthetic approach simplifies the discovery of radioligands. To demonstrate the breadth of applicability of this technique, we perform rapid synthesis of 20 tritiated and 10 carbon-11-labelled complex pharmaceuticals and PET radioligands, including a one-step radiosynthesis of the clinically used compounds [11C]UCB-J and [11C]PHNO. We further outline the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. We also demonstrate this protocol for the installation of other diverse and pharmaceutically useful isotopes, including carbon-14, carbon-13 and deuterium.


Assuntos
Técnicas de Química Sintética , Ligantes , Processos Fotoquímicos , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos/química , Alquilação , Radioisótopos de Carbono/química , Glipizida/análogos & derivados , Glipizida/química , Metilação , Oxirredução
2.
Bioorg Med Chem Lett ; 80: 129120, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36587872

RESUMO

GPR88 is an orphan G protein-coupled receptor which has been implicated in a number of striatal-associated disorders. Herein we describe the synthesis and pharmacological characterization of the first GPR88 radioligand, [3H]RTI-33, derived from a synthetic agonist RTI-13951-33. [3H]RTI-33 has a specific activity of 83.4 Ci/mmol and showed one-site, saturable binding (KD of 85 nM) in membranes prepared from stable PPLS-HA-hGPR88-CHO cells. A competition binding assay was developed to determine binding affinities of several known GPR88 agonists. This radioligand represents a powerful tool for future mechanistic and cell-based ligand-receptor interaction studies of GPR88.


Assuntos
Proteínas de Transporte , Receptores Acoplados a Proteínas G , Cricetinae , Animais , Cricetulus , Receptores Acoplados a Proteínas G/agonistas , Ensaio Radioligante
3.
Nature ; 529(7585): 195-9, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26762456

RESUMO

A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process--ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials--to elucidate a drug molecule's metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain (14)C or (3)H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium ((3)H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalysed method for the direct (3)H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.


Assuntos
Ferro/química , Marcação por Isótopo/métodos , Preparações Farmacêuticas/química , Trítio/química , Catálise , Deutério/química , Descoberta de Drogas , Irídio/química , Preparações Farmacêuticas/metabolismo
4.
J Labelled Comp Radiopharm ; 63(6): 247-265, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31410875

RESUMO

The highlights of C (sp2 )-H hydrogen isotope exchange (HIE) methods developed over the past 10 years are summarized in this review. Major developments include improved Ir(I) catalysts with greater functional group and solvent compatibility and the development of novel base metal catalysts for HIE. In addition, a number of novel Ru-based catalysts have been developed with promising activity. In the area of Pt- and Pd-catalysed exchange, in addition to new advances on heterogeneous Pt- and Pd-catalysed HIE by Sajiki and Shevchenko, a number of groups have reported on homogenous catalysts of Pt and Pd that show an interesting activity and selectivity.


Assuntos
Hidrogênio/química , Isótopos/química , Catálise
5.
J Labelled Comp Radiopharm ; 63(6): 296-307, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31950546

RESUMO

Hydrogen isotope exchange (HIE) has played an increasingly important role in deuteration and tritiation of compounds in the pharmaceutical industry. Transition metal-catalyzed HIE methods have gained considerable attention in the past decades, and most of these methods were comprehensively reviewed in 2010 in a special JLCR issue. It covered a wide variety of HIE catalysis systems involving precious metal catalysts, and a relatively small percentage of base metal catalysts, with a major focus on heterogeneous nickel. While base metal catalysts have remained underdeveloped for HIE chemistry relative to second and third row transition metal catalysts, in recent years, the first examples of homogeneous iron, nickel, and cobalt catalysts have been introduced to the field. Hence, in this review, we describe the recent development of base metal catalysts for HIE and their applications in isotopic labeling of pharmaceutical compounds. These research efforts have resulted in the development of labeling approaches that complement traditional methods in terms of activity and selectivity, thus diversifying the methodologies available for isotope chemists.


Assuntos
Hidrogênio/química , Isótopos/química , Metais/química , Catálise
6.
J Labelled Comp Radiopharm ; 63(4): 196-202, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017204

RESUMO

[3 H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp2 CH bond ortho to the methyl ester functionality were developed through deuterium modeling studies through a catalyst screen. Optimized conditions so obtained were then utilized with tritium gas to generate [3 H]genipin at a specific activity of 18.5 Ci/mmol. Racemic [14 C]genipin was prepared in eight steps in overall 5.4% radiochemical yield from potassium [14 C]cyanide.


Assuntos
Radioisótopos de Carbono/química , Iridoides/química , Iridoides/síntese química , Trítio/química , Catálise , Técnicas de Química Sintética , Irídio/química , Marcação por Isótopo , Radioquímica
7.
J Am Chem Soc ; 141(12): 5034-5044, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30827090

RESUMO

The synthesis and spectroscopic characterization of a family of Ni-X (X = Cl, Br, I, H) complexes supported by the bulky α-diimine chelate N, N'-bis(1 R,2 R,3 R,5 S)-(-)-isopinocampheyl-2,3-butanediimine (ipcADI) are described. Diimine-supported, three-coordinate nickel(I)-X complexes have been proposed as key intermediates in a host of catalytic transformations such as C-C and C-heteroatom cross-coupling and C-H functionalization but have until now remained synthetically elusive. A combination of structural, spectroscopic, electrochemical, and computational studies were used to establish the electronic structure of each monomeric [(ipcADI)NiX] (X = Cl, Br, I) complex as a nickel(I) derivative supported by a redox-neutral α-diimine chelate. The dimeric nickel hydride, [(ipcADI)Ni(µ2-H)]2, was prepared and characterized by X-ray diffraction; however, magnetic measurements and 1H NMR spectroscopy support monomer formation at ambient temperature in THF solution. This nickel hydride was used as a precatalyst for the hydrogen isotope exchange (HIE) of C-H bonds in arenes and pharmaceuticals. By virtue of the multisite reactivity and high efficiency, the new nickel precatalyst provided unprecedented high specific activities (50-99 Ci/mmol) in radiolabeling, meeting the threshold required for radioligand binding assays. Use of air-stable and readily synthesized nickel precursor, [(ipcADI)NiBr2], broad functional group tolerance, and compatibility with polar protic solvents are additional assets of the nickel-catalyzed HIE method.


Assuntos
Halogênios/química , Hidrogênio/química , Iminas/química , Níquel/química , Preparações Farmacêuticas/química , Catálise , Técnicas de Química Sintética , Isótopos/química , Ligantes , Modelos Moleculares , Conformação Molecular
8.
Mol Pharm ; 16(6): 2579-2589, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31021639

RESUMO

Molecular interactions between the active pharmaceutical ingredient and polymer have potentially substantial impacts on the physical stability of amorphous solid dispersions (ASDs), presumably by manipulating molecular mobility and miscibility. However, structural details for understanding the nature of the molecular contacts and mechanistic roles in various physicochemical and thermodynamic events often remain unclear. This study provides a spectroscopic characterization of posaconazole (POSA) formulations, a second-generation triazole antifungal drug (Noxafil, Merck & Co., Inc., Kenilworth, NJ, USA), at molecular resolution. One- and two-dimensional (2D) solid-state NMR (ssNMR) techniques including spectral editing, heteronuclear 1H-13C, 19F-13C, 15N-13C, and 19F-1H polarization transfer, and spin correlation and ultrafast magic angle spinning, together with the isotopic labeling strategy, were utilized to uncover molecular details in POSA ASDs in a site-specific manner. Active groups in triazole and difluorophenyl rings exhibited rich but distinct categories of interactions with two polymers, hypromellose acetate succinate and hypromellose phthalate, including intermolecular O-H···O═C and O-H···F-C hydrogen bonding, π-π aromatic packing, and electrostatic interaction. Interestingly, the chlorine-to-fluorine substituent in POSA, one of the major structural differences from itraconazole that could facilitate binding to the biological target, offers an additional contact with the polymer. These findings exhibit 2D ssNMR as a sensitive technique for probing sub-nanometer structures of pharmaceutical materials and provide a structural basis for optimizing the type and strength of drug-polymer interactions in the design of amorphous formulations.


Assuntos
Carbono/química , Coloides/química , Triazóis/química , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética
9.
J Labelled Comp Radiopharm ; 62(11): 690-694, 2019 09.
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.


Assuntos
Deutério/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Técnicas de Química Sintética , Terminologia como Assunto
10.
J Am Chem Soc ; 140(6): 1990-1993, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29377684

RESUMO

Methods to incorporate deuterium and tritium atoms into organic molecules are valuable for medicinal chemistry. The prevalence of pyridines and diazines in pharmaceuticals means that new ways to label these heterocycles will present opportunities in drug design and facilitate absorption, distribution, metabolism, and excretion (ADME) studies. A broadly applicable protocol is presented wherein pyridines, diazines, and pharmaceuticals are converted into heterocyclic phosphonium salts and then isotopically labeled. The isotopes are incorporated in high yields and, in general, with exclusive regioselectivity.


Assuntos
Deutério/química , Compostos Heterocíclicos/química , Preparações Farmacêuticas/química , Piridinas/química , Trítio/química , Marcação por Isótopo/métodos , Compostos Organofosforados/química , Estereoisomerismo
11.
Chemistry ; 24(28): 7133-7136, 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29604145

RESUMO

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on 2 H, 13 C, and 15 N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of 34 S. The synthetic utility of 34 S was demonstrated with the efficient synthesis of [34 S]phosphorothioates [34 S2 ]-PS-ODNs-TTT and [13 C, 15 N, 34 S]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [34 S]phosphorothioates using elemental 34 S without isotope dilution was developed.


Assuntos
Marcação por Isótopo/métodos , Isótopos/síntese química , Descoberta de Drogas , Isótopos/química , Oxirredução
12.
Bioorg Med Chem Lett ; 28(11): 2029-2034, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29748051

RESUMO

Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 µM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 µM h; F% = 70).


Assuntos
Antineoplásicos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Anal Biochem ; 518: 9-15, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27815077

RESUMO

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created an urgent need for new therapeutic agents capable of combating this threat. We have previously reported on the discovery of novel inhibitors targeting enzymes involved in the biosynthesis of wall teichoic acid (WTA) and demonstrated that these agents can restore ß-lactam efficacy against MRSA. In those previous reports pathway engagement of inhibitors was demonstrated by reduction in WTA levels measured by polyacrylamide gel electrophoresis. To enable a more rigorous analysis of these inhibitors we sought to develop a quantitative method for measuring whole-cell reductions in WTA. Herein we describe a robust methodology for hydrolyzing polymeric WTA to the monomeric component ribitol-N-acetylglucosamine coupled with measurement by LC-MS/MS. Critical elements of the protocol were found to include the time and temperature of hydrofluoric acid-mediated hydrolysis of polymeric WTA and optimization of these parameters is fully described. Most significantly, the assay enabled accurate and reproducible measurement of depletion EC50s for tunicamycin and representatives from the novel class of TarO inhibitors, the tarocins. The method described can readily be adapted to quantifying levels of WTA in tissue homogenates from a murine model of infection, highlighting the applicability for both in vitro and in vivo characterizations.


Assuntos
Espectrometria de Massas/métodos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Ácidos Teicoicos/metabolismo , Cromatografia Líquida/métodos , Staphylococcus aureus Resistente à Meticilina/química , Ácidos Teicoicos/química , Tunicamicina/farmacologia
14.
J Labelled Comp Radiopharm ; 59(10): 386-90, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27334864

RESUMO

An efficient synthesis for [(14) C]Omarigliptin (MK-3102) is described. The initial synthesis of a key (14) C-pyrazole moiety did not work due to the lack of stability of (14) C-DMF-DMA reagent. Thus, a new radiolabeled synthon, (14) C-biphenylmethylformate, was synthesized from (14) C-sodium formate in one step in 92% yield and successfully used in construction of the key (14) C-pyrazole moiety. Regioselective N-sulfonation of the pyrazole moiety was achieved through a dehydration-sulfonation-isomerization sequence. [(14) C]MK 3102 was synthesized in five steps from (14) C-biphenylmethylformate with 25% overall yield.


Assuntos
Radioisótopos de Carbono , Compostos Heterocíclicos com 2 Anéis/síntese química , Piranos/síntese química , Técnicas de Química Sintética , Compostos Heterocíclicos com 2 Anéis/química , Isomerismo , Marcação por Isótopo , Piranos/química
15.
J Labelled Comp Radiopharm ; 63(6): 246, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32330319
16.
J Labelled Comp Radiopharm ; 58(1): 20-2, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25616231

RESUMO

Radiolabeled steroid derivative 1 was successfully prepared using a Horner-Wadsworth-Emmons approach: a [(14) C]-label was efficiently incorporated into the C-18 position of the molecule. Previously published procedures employing other olefination methods are either not applicable due to unavailability of [(14) C]-precursors or suffer from poor reactivity.


Assuntos
Alcenos/química , Esteroides/química , Radioisótopos de Carbono/química , Técnicas de Química Sintética/métodos
17.
J Labelled Comp Radiopharm ; 58(7): 291-8, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26014438

RESUMO

Compounds containing tritium are widely used across the drug discovery and development landscape. These materials are widely utilized because they can be efficiently synthesized and produced at high specific activity. Results from internally calibrated (3)H and (1)H nuclear magnetic resonance (NMR) spectroscopy suggests that at least in some cases, this calibrated approach could supplement or potentially replace radio-high-performance liquid chromatography for radiochemical purity, dilution and scintillation counting for the measurement of radioactivity per volume, and liquid chromatography/mass spectrometry analysis for the determination of specific activity. In summary, the NMR-derived values agreed with those from the standard approaches to within 1% to 9% for solution count and specific activity. Additionally, the NMR-derived values for radiochemical purity deviated by less than 5%. A benefit of this method is that these values may be calculated at the same time that (3)H NMR analysis provides the location and distribution of tritium atoms within the molecule. Presented and discussed here is the application of this method, advantages and disadvantages of the approach, and a rationale for utilizing internally calibrated (1)H and (3)H NMR spectroscopy for specific activity, radioactive concentration, and radiochemical purity whenever acquiring (3)H NMR for tritium location.


Assuntos
Espectroscopia de Prótons por Ressonância Magnética/métodos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/normas , Trítio/química
18.
J Labelled Comp Radiopharm ; 57(11): 632-6, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25251383

RESUMO

SCH 900567 is a specific inhibitor of tumor necrosis factor-alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [(3) H]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope-labeled [(13) C3 , (15) N]SCH 900567 was requested by the bioanalytical group as an internal standard for Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development as well as by the drug metabolism and pharmacokinetics group for a potential microdose study. [(13) C3 , (15) N]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [(14) C]SCH 900567 was needed for a quantitative whole body autoradiography studies and was prepared from unlabeled Active Pharmaceutical Ingredient (API) via hydrolysis of the hydantoin moiety followed by rebuilding the hydantoin ring using potassium [(14) C]cyanate to give the desired product in 42.8% overall yield. Activation of the hydantoin moiety of SCH 900567 to achieve hydrolysis followed by derivatization of the resulting amino acid to avoid decarboxylation during cyclization is also discussed.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Hidantoínas/síntese química , Isoindóis/síntese química , Compostos Radiofarmacêuticos/síntese química , Proteína ADAM17 , Radioisótopos de Carbono/química , Hidantoínas/farmacocinética , Isoindóis/farmacocinética , Radioisótopos de Nitrogênio/química , Trítio/química
19.
Bioorg Med Chem Lett ; 23(24): 6585-7, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24252545
20.
J Labelled Comp Radiopharm ; 56(9-10): 480-4, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24285525

RESUMO

The syntheses of [(3) H]SCH 444877, [(2) H4 ]SCH 444877, and [(14) C]SCH 444877 are described. [(3) H]SCH 444877 was prepared in three steps from tritium gas. [(2) H4 ]SCH 444877 was synthesized from [(2) H4 ]ethanolamine in four steps with an overall yield of 40%. [(14) C]SCH 444877 was prepared from barium [(14) C]cyanamide in 10 steps with an overall yield of 8.1%.


Assuntos
Deutério/química , Guanina/análogos & derivados , Imidazóis/química , Imidazóis/síntese química , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/síntese química , Trítio/química , Radioisótopos de Carbono/química , Técnicas de Química Sintética , Guanina/síntese química , Guanina/química , Marcação por Isótopo , Padrões de Referência
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