Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
1.
Nature ; 609(7926): 408-415, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35831509

RESUMO

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .


Assuntos
Microscopia Crioeletrônica , Peptídeos e Proteínas de Sinalização Intracelular , Complexos Multiproteicos , Proteína Fosfatase 1 , Proteínas ras , Motivos de Aminoácidos , Sítios de Ligação , Guanosina Trifosfato/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Mutação de Sentido Incorreto , Fosforilação , Ligação Proteica , Proteína Fosfatase 1/química , Proteína Fosfatase 1/metabolismo , Proteína Fosfatase 1/ultraestrutura , Estabilidade Proteica , Quinases raf , Proteínas ras/química , Proteínas ras/metabolismo , Proteínas ras/ultraestrutura
2.
Nat Chem Biol ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965384

RESUMO

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.

3.
Bioorg Med Chem Lett ; 29(17): 2503-2510, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327531

RESUMO

Cancer cells reprogram their metabolism to support growth and to mitigate cellular stressors. The serine synthesis pathway has been identified as a metabolic pathway frequently altered in cancers and there has been considerable interest in developing pharmacological agents to target this pathway. Here, we report a series of indole amides that inhibit human 3-phosphoglycerate dehydrogenase (PHGDH), the enzyme that catalyzes the first committed step of the serine synthesis pathway. Using X-ray crystallography, we show that the indole amides bind the NAD+ pocket of PHGDH. Through structure-based optimization we were able to develop compounds with low nanomolar affinities for PHGDH in an enzymatic IC50 assay. In cellular assays, the most potent compounds inhibited de novo serine synthesis with low micromolar to sub-micromolar activities and these compounds successfully abrogated the proliferation of cancer cells in serine free media. The indole amide series reported here represent an important improvement over previously published PHGDH inhibitors as they are markedly more potent and their mechanism of action is better defined.


Assuntos
Amidas/química , Inibidores Enzimáticos/química , Indóis/química , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Serina/biossíntese , Amidas/metabolismo , Amidas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Dinâmica Molecular , Fosfoglicerato Desidrogenase/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
4.
J Neurosci ; 34(24): 8336-46, 2014 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-24920637

RESUMO

BACE, a ß-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the ß-secretase pathway and a lowering of CNS amyloid-ß (Aß) levels. The interaction of the ß-secretase and α-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated Aß and soluble APPß (sAPPß), with increased newly generated sAPPα. A stable isotope labeling kinetics experiment in NHPs was performed with a (13)C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPPα, sAPPß, and Aß in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPß, and Aß were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPPß and sAPPα kinetics were similar, but both significantly slower than Aß. BACE inhibition resulted in decreased labeled sAPPß and Aß in CSF, without observable changes in labeled CSF sAPPα. ELISA concentrations of sAPPß and Aß both decreased and sAPPα increased. sAPPα increased by ELISA, with no difference by labeled sAPPα kinetics indicating increases in product may be due to APP shunting from the ß-secretase to the α-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.


Assuntos
Secretases da Proteína Precursora do Amiloide/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Sistema Nervoso Central/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Isótopos de Carbono/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Imunoprecipitação , Leucina/metabolismo , Macaca mulatta , Espectrometria de Massas , Neuroblastoma , Fragmentos de Peptídeos , Transfecção
5.
ACS Med Chem Lett ; 15(4): 524-532, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38628784

RESUMO

Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and is appropriate for in vivo evaluation of the ENL YEATS inhibition mechanism in AML.

6.
bioRxiv ; 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-37961297

RESUMO

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here, we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain of function mutation p.E1099K, resulting in growth suppression, apoptosis, and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 in a covalent and reversible manner to recruit the SCF FBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCF FBXO22 . Overall, we present a highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.

7.
Top Curr Chem ; 317: 83-114, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-21647837

RESUMO

Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade. We review here how we have used highly structure-driven fragment-based approaches to complement more traditional lead discovery to tackle high priority targets and those struggling for leads. Combining biomolecular nuclear magnetic resonance (NMR), X-ray crystallography, and molecular modeling with structure-assisted chemistry and innovative biology as an integrated approach for FBDD can solve very difficult problems, as illustrated in this chapter. Here, a successful FBDD campaign is described that has allowed the development of a clinical candidate for BACE-1, a challenging CNS drug target. Crucial to this achievement were the initial identification of a ligand-efficient isothiourea fragment through target-based NMR screening and the determination of its X-ray crystal structure in complex with BACE-1, which revealed an extensive H-bond network with the two active site aspartate residues. This detailed 3D structural information then enabled the design and validation of novel, chemically stable and accessible heterocyclic acylguanidines as aspartic acid protease inhibitor cores. Structure-assisted fragment hit-to-lead optimization yielded iminoheterocyclic BACE-1 inhibitors that possess desirable molecular properties as potential therapeutic agents to test the amyloid hypothesis of Alzheimer's disease in a clinical setting.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/farmacologia , Ressonância Magnética Nuclear Biomolecular , Bibliotecas de Moléculas Pequenas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala , Modelos Moleculares , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 22(7): 2444-9, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22390835
9.
ACS Med Chem Lett ; 13(3): 377-387, 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35300079

RESUMO

Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 inhibitor, TDI-6118 (compound 5). Additionally, in the course of our attempts to optimize this compound, we discovered TDI-11904 (compound 21), a novel, highly potent, and peripherally active EZH2 inhibitor based on a 7 member ring structure.

10.
Cancer Discov ; 12(11): 2684-2709, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36053276

RESUMO

The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach. SIGNIFICANCE: AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.


Assuntos
Leucemia Mieloide Aguda , Lisina , Humanos , Leucemia Mieloide Aguda/genética , Histonas/metabolismo , Cromatina , Proteína de Leucina Linfoide-Mieloide/metabolismo
11.
Bioorg Med Chem Lett ; 21(8): 2497-501, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21398125

RESUMO

Antagonism of the adenosine A(2A) receptor affords a possible treatment of Parkinson's disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A(1)) A(2A) antagonist activity. Structure-activity relationships are described for this series.


Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Receptor A2A de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Humanos , Doença de Parkinson/tratamento farmacológico , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/uso terapêutico , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-Atividade
12.
Cancer Res ; 81(8): 2002-2014, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33632898

RESUMO

Pancreatic adenocarcinoma (PDAC) epitomizes a deadly cancer driven by abnormal KRAS signaling. Here, we show that the eIF4A RNA helicase is required for translation of key KRAS signaling molecules and that pharmacological inhibition of eIF4A has single-agent activity against murine and human PDAC models at safe dose levels. EIF4A was uniquely required for the translation of mRNAs with long and highly structured 5' untranslated regions, including those with multiple G-quadruplex elements. Computational analyses identified these features in mRNAs encoding KRAS and key downstream molecules. Transcriptome-scale ribosome footprinting accurately identified eIF4A-dependent mRNAs in PDAC, including critical KRAS signaling molecules such as PI3K, RALA, RAC2, MET, MYC, and YAP1. These findings contrast with a recent study that relied on an older method, polysome fractionation, and implicated redox-related genes as eIF4A clients. Together, our findings highlight the power of ribosome footprinting in conjunction with deep RNA sequencing in accurately decoding translational control mechanisms and define the therapeutic mechanism of eIF4A inhibitors in PDAC. SIGNIFICANCE: These findings document the coordinate, eIF4A-dependent translation of RAS-related oncogenic signaling molecules and demonstrate therapeutic efficacy of eIF4A blockade in pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/metabolismo , Fator de Iniciação 4A em Eucariotos/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Mensageiro/metabolismo , Ribossomos/metabolismo , Regiões 5' não Traduzidas , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Cicloeximida/farmacologia , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Quadruplex G , Genes ras/genética , Humanos , Camundongos , Camundongos Nus , Mutação , Transplante de Neoplasias , Oxirredução , Neoplasias Pancreáticas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Polirribossomos/metabolismo , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Helicases , Análise de Sequência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma , Triterpenos/farmacologia , Proteínas de Sinalização YAP , Proteínas rac de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas ral de Ligação ao GTP/genética , Proteínas ral de Ligação ao GTP/metabolismo , Proteína RAC2 de Ligação ao GTP
14.
J Pharmacol Exp Ther ; 330(1): 294-303, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19332567

RESUMO

The adenosine A(2A) receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and have >1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A(2A) receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A(2A) receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine], suggesting that they inhibit A(2A) receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A(2A) receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A(2A) receptor antagonists and provide further evidence of the potential therapeutic benefits of A(2A) receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).


Assuntos
Antagonistas do Receptor A2 de Adenosina , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Transtornos dos Movimentos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Transtorno Depressivo/metabolismo , Humanos , Masculino , Camundongos , Transtornos dos Movimentos/metabolismo , Fármacos Neuroprotetores/química , Pirimidinas/química , Ratos , Receptor A2A de Adenosina/metabolismo , Triazóis/química
15.
Bioorg Med Chem Lett ; 19(3): 967-71, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19109019

RESUMO

Antagonism of the adenosine A(2a) receptor offers great promise in the treatment of Parkinson's disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A(1)) A(2a) antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure-activity relationships and plasma levels are described for this series.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Doença de Parkinson/tratamento farmacológico , Pirimidinas/farmacologia , Triazóis/síntese química , Administração Oral , Animais , Área Sob a Curva , Catalepsia , Química Farmacêutica/métodos , Desenho de Fármacos , Haloperidol/farmacologia , Modelos Químicos , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/farmacologia
16.
Bioorg Med Chem Lett ; 19(21): 6018-22, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19800231

RESUMO

Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.


Assuntos
Antidiuréticos/química , Antagonistas dos Receptores de Hormônios Antidiuréticos , Quinolinas/química , Sulfonamidas/química , Animais , Antidiuréticos/síntese química , Antidiuréticos/farmacologia , Humanos , Quinolinas/síntese química , Quinolinas/farmacologia , Ratos , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia
17.
Bioorg Med Chem Lett ; 18(3): 1146-50, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18160282

RESUMO

We have derived a novel series of neuropeptide Y (NPY) Y5 receptor antagonists from the biphenylurea 3. Cyclohexylurea 21c, a member of the series, is a potent NPY Y5 receptor antagonist that exhibits excellent pharmacokinetic parameters in rats and dogs. On chronic oral administration to diet-induced obese rats, 21c displayed an anti-obesity profile, causing a modest reduction in food intake, a significant decrease in body weight gain, a decrease in adipose mass, and an increase in lean tissue mass.


Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Ureia , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/química , Técnicas de Química Combinatória , Cães , Humanos , Camundongos , Estrutura Molecular , Obesidade/induzido quimicamente , Ratos , Relação Estrutura-Atividade , Ureia/administração & dosagem , Ureia/análogos & derivados , Ureia/síntese química , Ureia/química , Ureia/farmacologia
18.
ACS Med Chem Lett ; 9(5): 457-461, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795759

RESUMO

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.

19.
J Med Chem ; 61(23): 10700-10708, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30388368

RESUMO

Herein we describe structure-activity relationship (SAR) and metabolite identification (Met-ID) studies that provided insight into the origin of time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4) by compound 1. Collectively, these efforts revealed that bioactivation of the fluoropyrimidine moiety of 1 led to reactive metabolite formation via oxidative defluorination and was responsible for the observed TDI. We discovered that substitution at both the 4- and 6-positions of the 5-fluoropyrimidine of 1 was necessary to ameliorate this TDI as exemplified by compound 19.


Assuntos
Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Animais , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Humanos , Cinética , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Distribuição Tecidual
20.
ACS Med Chem Lett ; 8(12): 1292-1297, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29259750

RESUMO

Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to MK-8718.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA