Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 67(5): 3935-3958, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38365209

RESUMO

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.


Assuntos
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidases/química , Invenções , Inibidores de Proteases/farmacologia , Amidas , Antivirais/farmacologia , Antivirais/química
2.
Sci Transl Med ; 15(684): eabn2038, 2023 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-36812345

RESUMO

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1+ cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4+ T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Antivirais/uso terapêutico , Apoptose , Morte Celular , Linfócitos T CD4-Positivos , Replicação Viral
3.
ACS Chem Biol ; 17(9): 2595-2604, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36044633

RESUMO

Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 ("inducer of cell death-1 and 2"), optimized for potency and selectivity from screening hits, were used to deconvolute the mechanism of action using a combination of chemoproteomic, biochemical, pharmacological, and genetic approaches. We determined that these compounds function by modulating dipeptidyl peptidase 9 (DPP9) and activating the caspase recruitment domain family member 8 (CARD8) inflammasome. Efficacy of ICeD-1 and ICeD-2 was dependent on HIV-1 protease activity and synergistic with efavirenz, which promotes premature activation of HIV-1 protease at high concentrations in infected cells. This in vitro synergy lowers the efficacious cell kill concentration of efavirenz to a clinically relevant dose at concentrations of ICeD-1 or ICeD-2 that do not result in complete DPP9 inhibition. These results suggest engagement of the pyroptotic pathway as a potential approach to eliminate HIV-1 infected cells.


Assuntos
Infecções por HIV , HIV-1 , Alcinos , Benzoxazinas , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Ciclopropanos , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Humanos , Inflamassomos/metabolismo , Leucócitos Mononucleares , Proteínas de Neoplasias/metabolismo
4.
J Am Coll Health ; 70(3): 818-823, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-32569511

RESUMO

ObjectiveTo understand the distribution of healthy and unhealthy food stores near historically black colleges and universities (HBCUs). Participants and methods: Using ArcGIS Pro's network analysis tools and ReferenceUSA database, this study characterized the healthy (favorable) and unhealthy (unfavorable) retail food stores within a 5-mile radius, 15-min driving, and 15-min walking distance from each HBCU in North Carolina. Results: Most retail food stores within a 5-mile buffer radius of the 10 HBCUs in North Carolina were unfavorable. Within 15-min driving from each HBCU, 1082 stores (76.0%) were unfavorable food stores, while 332 (24.0%) were favorable. Additionally, there were four favorable and 35 unfavorable retail food stores within the 15-min walking distance of each HBCU. Conclusions: Favorable food retail stores around HBCUs in North Carolina are limited. Researchers, policy makers, and community stakeholders should work together to improve food environments surrounding HBCUs.


Assuntos
Negro ou Afro-Americano , Sistemas de Informação Geográfica , População Negra , Humanos , Estudantes , Universidades
5.
Gerontol Geriatr Med ; 7: 2333721421990150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33532515

RESUMO

Informal caregivers form a shadow workforce projected to become even more essential as the U.S. population ages. Most are untrained in the role and manage caregiving with competing life demands that compound burden and threaten the welfare of the older adults in their care. The 12-item Zarit Burden Interview measure was employed to investigate differences in subjective burden before and during the Covid-19 pandemic among adult children who are primary informal caregivers of a parent. Additionally, this study explored family composition to determine if the presence of siblings or dependent children affected burden scores. A convenience sample (N = 77) reported significantly more burden since the onset of the Covid-19 pandemic when compared to pre-pandemic burden. Since the pandemic began, those with living siblings reported less burden than those without siblings, while there was no difference in burden between sandwich generation caregivers and those providing care only for a parent. This study's results point to the role family plays in resilience during a crisis and emphasizes the need to promote efficient supports and networks to alleviate caregiver burden.

6.
Environ Manage ; 62(6): 1007-1024, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30171327

RESUMO

The persistence of freshwater degradation has necessitated the growth of an expansive stream and wetland restoration industry, yet restoration prioritization at broad spatial extents is still limited and ad-hoc restoration prevails. The River Basin Restoration Prioritization tool has been developed to incorporate vetted, distributed data models into a catchment scale restoration prioritization framework. Catchment baseline condition and potential improvement with restoration activity is calculated for all National Hydrography Dataset stream reaches and catchments in North Carolina and compared to other catchments within the river subbasin to assess where restoration efforts may best be focused. Hydrologic, water quality, and aquatic habitat quality conditions are assessed with peak flood flow, nitrogen and phosphorus loading, and aquatic species distribution models. The modular nature of the tool leaves ample opportunity for future incorporation of novel and improved datasets to better represent the holistic health of a watershed, and the nature of the datasets used herein allow this framework to be applied at much broader scales than North Carolina.


Assuntos
Big Data , Conservação dos Recursos Hídricos , Rios/química , Ecossistema , Monitoramento Ambiental , Hidrologia , Nitrogênio/análise , North Carolina , Fósforo/análise , Qualidade da Água , Áreas Alagadas
7.
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.

8.
Bioorg Med Chem Lett ; 27(23): 5167-5171, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29113762

RESUMO

We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Ki = 22.4 µM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfodiesterase/química , Animais , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacocinética , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade
9.
ACS Med Chem Lett ; 7(7): 702-7, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27437081

RESUMO

A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.

10.
Environ Sci Technol ; 46(15): 8115-22, 2012 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-22788537

RESUMO

Surface coal mining is the dominant form of land cover change in Central Appalachia, yet the extent to which surface coal mine runoff is polluting regional rivers is currently unknown. We mapped surface mining from 1976 to 2005 for a 19,581 km(2) area of southern West Virginia and linked these maps with water quality and biological data for 223 streams. The extent of surface mining within catchments is highly correlated with the ionic strength and sulfate concentrations of receiving streams. Generalized additive models were used to estimate the amount of watershed mining, stream ionic strength, or sulfate concentrations beyond which biological impairment (based on state biocriteria) is likely. We find this threshold is reached once surface coal mines occupy >5.4% of their contributing watershed area, ionic strength exceeds 308 µS cm(-1), or sulfate concentrations exceed 50 mg L(-1). Significant losses of many intolerant macroinvertebrate taxa occur when as little as 2.2% of contributing catchments are mined. As of 2005, 5% of the land area of southern WV was converted to surface mines, 6% of regional streams were buried in valley fills, and 22% of the regional stream network length drained watersheds with >5.4% of their surface area converted to mines.


Assuntos
Minas de Carvão , Poluentes da Água/análise , Animais , Região dos Apalaches , Invertebrados , Concentração Osmolar , Rios , Qualidade da Água , West Virginia
11.
Proc Natl Acad Sci U S A ; 108(34): 13957-62, 2011 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-21873184

RESUMO

In the Luangwa Valley, Zambia, persistent poverty and hunger present linked challenges to rural development and biodiversity conservation. Both household coping strategies and larger-scale economic development efforts have caused severe natural resource degradation that limits future economic opportunities and endangers ecosystem services. A model based on a business infrastructure has been developed to promote and maintain sustainable agricultural and natural resource management practices, leading to direct and indirect conservation outcomes. The Community Markets for Conservation (COMACO) model operates primarily with communities surrounding national parks, strengthening conservation benefits produced by these protected areas. COMACO first identifies the least food-secure households and trains them in sustainable agricultural practices that minimize threats to natural resources while meeting household needs. In addition, COMACO identifies people responsible for severe natural resource depletion and trains them to generate alternative income sources. In an effort to maintain compliance with these practices, COMACO provides extension support and access to high-value markets that would otherwise be inaccessible to participants. Because the model is continually evolving via adaptive management, success or failure of the model as a whole is difficult to quantify at this early stage. We therefore test specific hypotheses and present data documenting the stabilization of previously declining wildlife populations; the meeting of thresholds of productivity that give COMACO access to stable, high-value markets and progress toward economic self-sufficiency; and the adoption of sustainable agricultural practices by participants and other community members. Together, these findings describe a unique, business-oriented model for poverty alleviation, food production, and biodiversity conservation.


Assuntos
Biodiversidade , Conservação dos Recursos Naturais/economia , Abastecimento de Alimentos/economia , Renda , Modelos Econômicos , Características de Residência , Animais , Animais Selvagens , Características da Família , Geografia , Dinâmica Populacional , Fatores de Tempo , Zâmbia
12.
ACS Chem Neurosci ; 2(7): 352-62, 2011 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22816022

RESUMO

A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.


Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Descoberta de Drogas/métodos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Animais , Benzopiranos/metabolismo , Disponibilidade Biológica , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Meia-Vida , Indicadores e Reagentes , Isomerismo , Ligadura , Macaca mulatta , Masculino , Neuralgia/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologia
13.
Bioorg Med Chem Lett ; 20(22): 6827-30, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20850973

RESUMO

A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.


Assuntos
Amidas/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Amidas/química , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 20(8): 2572-6, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20299218

RESUMO

A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Macaca mulatta , Quinolinas/química , Quinolinas/farmacocinética , Ratos
15.
J Pharmacol Exp Ther ; 333(1): 152-60, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20065019

RESUMO

Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos de Espiro/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Autorradiografia , Ligação Competitiva , Transporte Biológico , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/líquido cefalorraquidiano , Linhagem Celular , Chlorocebus aethiops , Feminino , Humanos , Cinética , Macaca mulatta , Masculino , Camundongos , Ensaio Radioligante , Receptores de Adrenomedulina , Receptores da Calcitonina/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas , Receptores de Peptídeos/metabolismo , Compostos de Espiro/sangue , Compostos de Espiro/líquido cefalorraquidiano , Vasodilatação/efeitos dos fármacos
16.
ACS Med Chem Lett ; 1(1): 24-9, 2010 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900170

RESUMO

Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.

17.
Bioorg Med Chem Lett ; 19(19): 5787-90, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19703767

RESUMO

A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.


Assuntos
Acetamidas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos de Espiro/química , Acetamidas/síntese química , Acetamidas/farmacologia , Animais , Linhagem Celular , Desenho de Fármacos , Humanos , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 19(1): 214-7, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19010673

RESUMO

Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indóis/síntese química , Compostos de Espiro/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Humanos , Indóis/farmacologia , Macaca mulatta , Oxindóis , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 18(23): 6122-5, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18947992

RESUMO

The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.


Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indanos/química , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Benzimidazóis/sangue , Benzimidazóis/química , Técnicas de Química Combinatória , Humanos , Macaca mulatta , Estrutura Molecular , Compostos de Espiro/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...