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1.
Circulation ; 148(2): 144-158, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37125593

RESUMO

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.


Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Adulto , Humanos , Anticolesterolemiantes/efeitos adversos , Colesterol , LDL-Colesterol , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Peptídeos/uso terapêutico , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo
2.
J Org Chem ; 85(3): 1466-1475, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31660743

RESUMO

The Myc transcription factor represents an "undruggable" target of high biological interest due to its central role in various cancers. An abbreviated form of the c-Myc protein, called Omomyc, consists of the Myc DNA-binding domain and a coiled-coil region to facilitate dimerization of the 90 amino acid polypeptide. Here we present our results to evaluate the synthesis of Omomyc using three complementary strategies: linear Fmoc solid-phase peptide synthesis (SPPS) using several advancements for difficult sequences, native chemical ligation from smaller peptide fragments, and a high-throughput bacterial expression and assay platform for rapid mutagenesis. This multifaceted approach allowed access to up to gram quantities of the mini-protein and permitted in vitro and in vivo SAR exploration of this modality. DNA-binding results and cellular activity confirm that Omomyc and analogues presented here, are potent binders of the E-box DNA engaged by Myc for transcriptional activation and that this 90-amino acid mini-protein is cell permeable and can inhibit proliferation of Myc-dependent cell lines. We also present additional results on covalent homodimerization through disulfide formation of the full-length mini-protein and show the coiled-coil region can be truncated while preserving both DNA binding and cellular activity. Altogether, our results highlight the ability of advanced peptide synthesis to achieve SAR tractability in a challenging synthetic modality.


Assuntos
DNA , Proteínas Proto-Oncogênicas c-myc , Linhagem Celular , DNA/metabolismo , Fragmentos de Peptídeos , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
3.
Bioorg Med Chem Lett ; 27(9): 2038-2046, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28285916

RESUMO

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.


Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/enzimologia , Piridonas/química , Piridonas/farmacologia , Animais , Cães , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Piridonas/farmacocinética
4.
J Labelled Comp Radiopharm ; 60(5): 263-269, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28185305

RESUMO

Fluorine-18-labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18 F]MK-6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2-step radiosynthesis of [18 F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FXFN . Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [18 F]fluoride (K[18 F]/K222 ) was performed by conventional heating, followed by acid deprotection and semipreparative high-performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170-250 mCi) of [18 F]MK-6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [18 F]fluoride) with a specific activity of 222 ± 67 GBq/µmol (6.0 ± 1.8 Ci/µmol) at the end of synthesis (90 minutes; n = 3). [18 F]MK-6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.


Assuntos
Radioisótopos de Flúor , Isoquinolinas/química , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Radioquímica/métodos , Compostos Radiofarmacêuticos/química , Halogenação , Humanos , Isoquinolinas/síntese química , Controle de Qualidade , Compostos Radiofarmacêuticos/síntese química
5.
Proc Natl Acad Sci U S A ; 107(48): 20648-51, 2010 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-20921367

RESUMO

The first enantioselective organocatalytic α-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated enamines, readily undergo allylic alkylation with a variety of commercially available allyl silanes. A reasonable latitude in both the ketone and allyl silane components is readily accommodated in this new transformation. Moreover, three new oxidatively stable imidazolidinone catalysts have been developed that allow cyclic ketones to successfully participate in this transformation. The new catalyst platform has also been exploited in the first catalytic enantioselective α-enolation and α-carbooxidation of ketones.

6.
Eur J Med Chem ; 224: 113686, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34303079

RESUMO

Pathway activating mutations of the transcription factor NRF2 and its negative regulator KEAP1 are strongly correlative with poor clinical outcome with pemetrexed/carbo(cis)platin/pembrolizumab (PCP) chemo-immunotherapy in lung cancer. Despite the strong genetic support and therapeutic potential for a NRF2 transcriptional inhibitor, currently there are no known direct inhibitors of the NRF2 protein or its complexes with MAF and/or DNA. Herein we describe the design of a novel and high-confidence homology model to guide a medicinal chemistry effort that resulted in the discovery of a series of peptides that demonstrate high affinity, selective binding to the Antioxidant Response Element (ARE) DNA and thereby displace NRF2-MAFG from its promoter, which is an inhibitory mechanism that to our knowledge has not been previously described. In addition to their activity in electrophoretic mobility shift (EMSA) and TR-FRET-based assays, we show significant dose-dependent ternary complex disruption of NRF2-MAFG binding to DNA by SPR, as well as cellular target engagement by thermal destabilization of HiBiT-tagged NRF2 in the NCI-H1944 NSCLC cell line upon digitonin permeabilization, and SAR studies leading to improved cellular stability. We report the characterization and unique profile of lead peptide 18, which we believe to be a useful in vitro tool to probe NRF2 biology in cancer cell lines and models, while also serving as an excellent starting point for additional in vivo optimization toward inhibition of NRF2-driven transcription to address a significant unmet medical need in non-small cell lung cancer (NSCLC).


Assuntos
DNA/química , Fator de Transcrição MafG/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Peptídeos/química , Elementos de Resposta Antioxidante/efeitos dos fármacos , DNA/metabolismo , Desenho de Fármacos , Estabilidade de Medicamentos , Ensaio de Desvio de Mobilidade Eletroforética , Meia-Vida , Células HeLa , Humanos , Fator de Transcrição MafG/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Relação Estrutura-Atividade
7.
J Med Chem ; 64(22): 16770-16800, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34704436

RESUMO

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.


Assuntos
Inibidores de PCSK9/farmacologia , Peptídeos Cíclicos/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Macaca fascicularis , Estrutura Molecular , Inibidores de PCSK9/química , Inibidores de PCSK9/farmacocinética , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Ratos , Relação Estrutura-Atividade
8.
FEBS Lett ; 594(10): 1467-1476, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32053209

RESUMO

Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini-protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10-fold more potent than Omomyc in inhibiting Myc-driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E-Box DNA in the promoters of Myc target genes and represses Myc-mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras/química , Transcrição Gênica/efeitos dos fármacos , Sequência de Aminoácidos , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular , Nucléolo Celular/metabolismo , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , Fragmentos de Peptídeos/isolamento & purificação , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética
9.
Mol Imaging Biol ; 22(1): 173-180, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31111397

RESUMO

PURPOSE: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies. PROCEDURES: MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 µg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose). RESULTS: MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 µg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 µg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 µGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 µSv/MBq, which is in the typical range for F-18 radiolabeled ligands. CONCLUSIONS: Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.


Assuntos
Doença de Alzheimer/patologia , Radioisótopos de Flúor/farmacocinética , Isoquinolinas/farmacocinética , Emaranhados Neurofibrilares/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radiometria/métodos , Imagem Corporal Total/métodos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Animais , Feminino , Voluntários Saudáveis , Humanos , Masculino , Emaranhados Neurofibrilares/metabolismo , Segurança do Paciente , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Distribuição Tecidual
10.
Angew Chem Int Ed Engl ; 48(24): 4349-53, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19434637

RESUMO

United in effort: The combined application of iminium (Im) and enamine (En) catalysts can effect a range of valuable asymmetric transformations including 1,2-hydroamination, -hydro-oxidation, and -amino-oxidation of olefins (see picture). An enantioselective organocascade catalysis was also applied in the synthesis of a complex natural product.


Assuntos
Alcenos/química , Sesquiterpenos/síntese química , Aminação , Catálise , Oxirredução , Sesquiterpenos/química , Sesquiterpenos de Guaiano , Estereoisomerismo
11.
Mol Cell Biol ; 39(22)2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31501275

RESUMO

The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by chromatin immunoprecipitation (CHIP). Here, we demonstrate by both a proximity ligation assay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo, Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Genes myc , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sequência de Aminoácidos , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Linhagem Celular , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina/métodos , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/farmacologia , Proteínas Recombinantes/farmacologia , Transcrição Gênica , Ativação Transcricional
12.
J Nucl Med ; 60(1): 107-114, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29880509

RESUMO

18F-MK-6240 (18F-labeled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective, subnanomolar-affinity PET tracer for imaging neurofibrillary tangles (NFTs). Plasma kinetics, brain uptake, and preliminary quantitative analysis of 18F-MK-6240 in healthy elderly (HE) subjects, subjects with clinically probable Alzheimer disease (AD), and subjects with amnestic mild cognitive impairment were characterized in a study that is, to our knowledge, the first to be performed on humans. Methods: Dynamic PET scans of up to 150 min were performed on 4 cognitively normal HE subjects, 4 AD subjects, and 2 amnestic mild cognitive impairment subjects after a bolus injection of 152-169 MBq of 18F-MK-6240 to evaluate tracer kinetics and distribution in brain. Regional SUV ratio (SUVR) and distribution volume ratio were determined using the cerebellar cortex as a reference region. Total distribution volume was assessed by compartmental modeling using radiometabolite-corrected input function in a subgroup of 6 subjects. Results:18F-MK-6240 had rapid brain uptake with a peak SUV of 3-5, followed by a uniformly quick washout from all brain regions in HE subjects; slower clearance was observed in regions commonly associated with NFT deposition in AD subjects. In AD subjects, SUVR between 60 and 90 min after injection was high (approximately 2-4) in regions associated with NFT deposition, whereas in HE subjects, SUVR was approximately 1 across all brain regions, suggesting high tracer selectivity for binding NFTs in vivo. 18F-MK-6240 total distribution volume was approximately 2- to 3-fold higher in neocortical and medial temporal brain regions of AD subjects than in HE subjects and stabilized by 60 min in both groups. Distribution volume ratio estimated by the Logan reference tissue model or compartmental modeling correlated well (R2 > 0.9) to SUVR from 60 to 90 min for AD subjects. Conclusion:18F-MK-6240 exhibited favorable kinetics and high binding levels to brain regions with a plausible pattern for NFT deposition in AD subjects. In comparison, negligible tracer binding was observed in HE subjects. This pilot study suggests that simplified ratio methods such as SUVR can be used to quantify NFT binding. These results support further clinical development of 18F-MK-6240 for potential application in longitudinal studies.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Encéfalo/patologia , Radioisótopos de Flúor , Isoquinolinas/metabolismo , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Isoquinolinas/sangue , Cinética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Traçadores Radioativos
13.
J Med Chem ; 60(16): 6771-6780, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28418656

RESUMO

High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure-activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter. These profiles allow teams to quickly assess hit series for desirable ADMET properties or suspected liabilities that may require significant optimization. Accordingly, these in silico data can direct ADMET experimentation and profoundly impact the progression of hit series. Several prospective examples are presented to substantiate the value of this approach.


Assuntos
Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Preparações Farmacêuticas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Farmacologia , Relação Quantitativa Estrutura-Atividade
14.
J Nucl Med ; 57(10): 1599-1606, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27230925

RESUMO

A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18F-MK-6240. METHODS: In vitro binding studies were conducted with 3H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with 18F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. RESULTS: The 3H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque-rich, NFT-poor AD brain homogenates. 3H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. CONCLUSION: 18F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients.


Assuntos
Isoquinolinas/química , Emaranhados Neurofibrilares , Tomografia por Emissão de Pósitrons/métodos , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Isoquinolinas/metabolismo , Macaca mulatta , Masculino , Traçadores Radioativos , Radioquímica
15.
J Med Chem ; 59(10): 4778-89, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27088900

RESUMO

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.


Assuntos
Descoberta de Drogas , Isoquinolinas/química , Imagem Molecular , Emaranhados Neurofibrilares/patologia , Tomografia por Emissão de Pósitrons , Radioisótopos de Flúor/química , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Estrutura Molecular , Emaranhados Neurofibrilares/metabolismo
16.
Org Lett ; 7(14): 2941-4, 2005 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-15987175

RESUMO

[reaction: see text] Chiral rhodium(II) catalysts used in asymmetric carbenoid chemistry can be efficiently heterogenized using a novel immobilization strategy. The immobilized catalysts display similar reactivity and stereoselectivity to their homogeneous counterparts and can be effectively recycled with limited loss in stereoselectivity.

17.
ChemMedChem ; 10(2): 245-52, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25469982

RESUMO

Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.


Assuntos
Inibidores de Integrase de HIV/química , Oxidiazóis/química , Pró-Fármacos/química , Pirimidinonas/química , Pirrolidinonas/química , Acetais/química , Animais , Área Sob a Curva , Carbonatos/química , Cães , Avaliação Pré-Clínica de Medicamentos , Integrase de HIV/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , HIV-1/enzimologia , Meia-Vida , Hepatócitos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Curva ROC , Raltegravir Potássico , Ratos , Ratos Wistar , Relação Estrutura-Atividade
18.
J Med Chem ; 58(20): 8154-65, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26397965

RESUMO

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.


Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Animais , Área Sob a Curva , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Integrase de HIV/efeitos dos fármacos , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacocinética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Modelos Moleculares , Pró-Fármacos , Piridonas/farmacocinética , Ratos
19.
Org Lett ; 5(4): 479-82, 2003 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-12583748

RESUMO

[reaction: see text] Heterogenization of dirhodium tetrakis((S)-N-dodecylbenzenesulfonyl)prolinate) (Rh(2)(S-DOSP)(4)) can be readily achieved on a pyridine functionalized highly cross-linked polystyrene resin. The immobilized complex is readily recycled and exhibits excellent catalytic activity for asymmetric intermolecular C-H activation by means of rhodium carbenoid induced C-H insertion.


Assuntos
Catálise , Compostos Organometálicos/química , Prolina/análogos & derivados , Prolina/química , Métodos , Resinas Sintéticas
20.
Pharmaceuticals (Basel) ; 7(2): 207-19, 2014 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-24566521

RESUMO

Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption.

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