Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Org Biomol Chem ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538747

RESUMO

A facile, DAST-mediated intramolecular cyclization of 3-hydroxy-3-(2-((3-methoxybenzyl)oxy)phenyl)indolin-2-one derivatives for the synthesis of spirooxindoles fused with dibenzoxepine moieties is described. The success of this reaction is highly dependent on the choice of solvent (promoted by DCM and 1,2-DCE) and the electronic nature of the pendant aromatic ring, which is favored by the presence of electron-donating substituents. The reaction is believed to proceed through an intramolecular Friedel-Crafts-type reaction. Various dibenzoxepine-fused spirooxindoles were successfully synthesized in up to 98% yield. This methodology provides libraries of structurally diverse and medicinally important small molecules that could aid in the search for new bioactive molecules.

2.
Bioorg Med Chem Lett ; 36: 127823, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33508465

RESUMO

GSK3532795 (formerly BMS-955176) is a second-generation HIV-1 maturation inhibitor that has shown broad spectrum antiviral activity and preclinical PK predictive of once-daily dosing in humans. Although efficacy was confirmed in clinical trials, the observation of gastrointestinal intolerability and the emergence of drug resistant virus in a Phase 2b clinical study led to the discontinuation of GSK3532795. As part of the effort to further map the maturation inhibitor pharmacophore and provide additional structural options, the evaluation of alternates to the C-3 phenyl substituent in this chemotype was pursued. A cyclohexene carboxylic acid provided exceptional inhibition of wild-type, V370A and ΔV370 mutant viruses in addition to a suitable PK profile following oral dosing to rats. In addition, a novel spiro[3.3]hept-5-ene was designed to extend the carboxylic acid further from the triterpenoid core while reducing side chain flexibility compared to the other alkyl substituents. This modification was shown to closely emulate the C-3 benzoic acid moiety of GSK3532795 from both a potency and PK perspective, providing a non-traditional, sp3-rich bioisostere of benzene. Herein, we detail additional modifications to the C-3 position of the triterpenoid core that offer effective replacements for the benzoic acid of GSK3532795 and capture the interplay between these new C-3 elements and C-17 modifications that contribute to enhanced polymorph coverage.

3.
Phys Rev Lett ; 125(20): 201101, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33258624

RESUMO

In this Letter, we show that multiband observations of stellar-mass binary black holes by the next generation of ground-based observatories (3G) and the space-based Laser Interferometer Space Antenna (LISA) would facilitate a comprehensive test of general relativity by simultaneously measuring all the post-Newtonian coefficients. Multiband observations would measure most of the known post-Newtonian phasing coefficients to an accuracy below a few percent-2 orders-of-magnitude better than the best bounds achievable from even "golden" binaries in the 3G or LISA bands. Such multiparameter bounds would play a pivotal role in constraining the parameter space of modified theories of gravity beyond general relativity.

5.
J Org Chem ; 85(17): 11519-11530, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32786620

RESUMO

Unnatural amino acids play an important role in peptide based drug discovery. Herein, we report a class of differentially protected azatryptophan derivatives synthesized from N-tosyl-3-haloazaindoles 1 and Fmoc-protected tert-butyl iodoalanine 2 via a Negishi coupling. Through ligand screening, Pd2(dba)3/XPhos was found to be a superior catalyst for the coupling of 1 with the zinc derivative of 2 to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate derivatives 3 in 69-91% isolated yields. In addition, we have demonstrated that the protecting groups, namely, Ts, Fmoc, and tBu, can be easily removed selectively.

7.
ACS Med Chem Lett ; 11(2): 172-178, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32071685

RESUMO

Novel imidazole-based TGFßR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFßR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFß-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFßR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

8.
J Am Chem Soc ; 142(6): 3094-3103, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927959

RESUMO

We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T1-S0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.

9.
ACS Biomater Sci Eng ; 6(2): 1102-1111, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33464864

RESUMO

Functionalized magnetic nanoparticles (MNPs) have attracted particular interest as potential drug delivery carriers as they offer dual advantage of delivering drugs to the target site complemented with magnetic hyperthermia-mediated therapy. Hyperbranched polymer-functionalized MNPs have the potential to perform a dual role of killing cancer cells by hyperthermia (by magnetite core) with apoptosis (by loaded niclosamide). These are formed by the co-precipitation of iron salts followed by aminocellulose grafting, branch growth, and PEGylation. NP formation was investigated by determining particle size, zeta potential, and microscopic (transmission electron microscopy, field-emission scanning electron microscopy, and atomic force microscopy) studies. Results showed that these nanocarriers were 107 ± 57 nm in size with a zeta potential of -18 mV and exist as NPs. Drug loading and encapsulation efficiency were calculated as 15.28 ± 2.72 and 76.41 ± 1.84%, respectively, using UV-vis spectroscopy. NPs were internalized into HCT116 cells as investigated using confocal microscopy and flow cytometry. Blank NPs at the dose of 200 µg/mL were found to be cytocompatible using hTERT cells and hemocompatible. The cell viability study suggested that niclosamide-loaded functionalized magnetic nanoparticles (NFMNPs) were more effective (7 times) than free niclosamide in killing colon cancer cells. Moreover, NFMNPs induced apoptosis in an immunofluorescence study of cleaved caspase-3. Exposure of NFMNPs to an alternating magnetic field (AMF) resulted in a slight increase in the rate of niclosamide release. AMF exposure drastically reduced cell viability due to dual effects of hyperthermia and niclosamide after treatment with NFMNPs. The potentiation of cell death due to dual effects of hyperthermia and niclosamide was further confirmed by Annexin-V/propidium iodide assay using flow cytometry. The results imply that niclosamide delivery through hyperbranched polymer-functionalized MNPs may serve as an effective strategy for the treatment of colorectal cancer.

11.
J Med Chem ; 62(21): 9931-9946, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.


Assuntos
Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Animais , Humanos , Células Jurkat , Camundongos , Modelos Moleculares , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
13.
J Med Chem ; 62(5): 2265-2285, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.


Assuntos
Ensaios Clínicos como Assunto , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Naftalenos/química , Naftalenos/farmacocinética , Ratos , Ratos Endogâmicos Lew , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética
14.
Dermatol Res Pract ; 2018: 5345390, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30186321

RESUMO

The study was conducted on skin of 24 buffaloes collected from slaughter house. The skin tissues were collected from dorsal, lateral, and ventral parts of head, neck, thorax, abdomen, and tail regions and fixed in 10% neutral buffered formalin. The tissues were processed for paraffin blocks preparation by acetone benzene schedule. The paraffin sections of 5-6 µm were cut with rotary microtome and stained with hematoxylin and eosin. The sweat glands in buffaloes were of saccular and simple coiled tubular type. Most of the sweat glands were associated with hair follicles and consisted of a coiled secretory portion (body) and a straight duct. The secretory portion was made up of glandular tubules, myoepithelium, and basement membrane. The duct portion had a narrow lumen and was lined by simple cuboidal epithelium. The glandular epithelium was simple squamous, simple cuboidal, or low columnar type depending upon their stage of secretary activity. Two types of sweat glands were observed, i.e., apocrine and merocrine. Large number of blood vessels and nerve fibers were observed in the vicinity of the sweat glands. In head, neck, and tail regions the maximum number of sweat glands/mm2 was observed in dorsal side which did not vary significantly (p<0.05) from lateral and ventral side. In abdomen region the number of sweat glands/mm2 was maximum on lateral region which varied significantly from ventral region (p<0.05). Overall, the maximum number of sweat glands/mm2 was in head region followed by abdomen, thorax, neck, and tail but without any significant (p<0.05) difference. Maximum sweat gland diameter was found in abdomen region followed by thorax, head, neck, and tail region.

15.
Biomacromolecules ; 19(3): 803-815, 2018 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-29451980

RESUMO

Synthetic lethality is a molecular-targeted therapy for selective killing of cancer cells. We exploited a lethal interaction between superoxide dismutase 1 inhibition and Bloom syndrome gene product (BLM) defect for the treatment of colorectal cancer (CRC) cells (HCT 116) with a customized lung cancer screen-1-loaded nanocarrier (LCS-1-NC). The drug LCS-1 has poor aqueous solubility. To overcome its limitations, a customized NC, composed of a magnetite core coated with three polymeric shells, namely, aminocellulose (AC), branched poly(amidoamine), and paraben-PEG, was developed for encapsulating LCS-1. Encapsulation efficiency and drug loading were found to be 74% and 8.2%, respectively. LCS-1-NC exhibited sustained release, with ∼85% of drug release in 24 h. Blank NC (0.5 mg/mL) exhibited cytocompatibility toward normal cells, mainly due to the AC layer. LCS-1-NC demonstrated high killing selectivity (104 times) toward BLM-deficient HCT 116 cells over BLM-proficient HCT 116 cells. Due to enhanced efficacy of the drug using NC, the sensitivity difference for BLM-deficient cells increased to 1.7 times in comparison to that with free LCS-1. LCS-1-NC induced persistent DNA damage and apoptosis, which demonstrates that LCS-1-NC effectively and preferentially killed BLM-deficient CRC cells. This is the first report on the development of a potential drug carrier to improve the therapeutic efficacy of LCS-1 for specific killing of CRC cells having BLM defects.


Assuntos
Antineoplásicos , Materiais Revestidos Biocompatíveis , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos , Nanopartículas de Magnetita , RecQ Helicases/deficiência , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacocinética , Materiais Revestidos Biocompatíveis/farmacologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico
16.
Curr Cancer Drug Targets ; 18(4): 337-346, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28669337

RESUMO

Cancer is an evolutionary disease with multiple genetic alterations, accumulated due to chromosomal instability and/or aneuploidy and it sometimes acquires drug-resistant phenotype also. Whole genome sequencing and mutational analysis helped in understanding the differences among persons for predisposition of a disease and its treatment non-responsiveness. Thus, molecular targeted therapies came into existence. Among them, the concept of synthetic lethality have enthralled great attention as it is a pragmatic approach towards exploiting cancer cell specific mutations to specifically kill cancer cells without affecting normal cells and thus enhancing anti-cancer drug therapeutic index. Thus, this approach helped in discovering new therapeutic molecules for development of precision medicine. Nanotechnology helped in delivering these molecules to the target site in an effective concentration thus reducing off target effects of drugs, dose and dosage frequency drugs. Researchers have tried to deliver siRNA targeting synthetic lethal partner for target cancer cell killing by incorporating it in nanoparticles and it has shown efficacy by preventing tumor progression. This review summarizes the brief introduction of synthetic lethality, and synthetic lethal gene interactions, with a major focus on its therapeutic anticancer potential with the application of nanotechnology for development of personalized medicine.


Assuntos
Pesquisa Biomédica/métodos , Nanomedicina/métodos , Neoplasias/terapia , Medicina de Precisão/métodos , Mutações Sintéticas Letais/genética , Animais , Antineoplásicos/administração & dosagem , Pesquisa Biomédica/tendências , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Nanomedicina/tendências , Nanotecnologia/métodos , Nanotecnologia/tendências , Neoplasias/genética , Neoplasias/metabolismo , Medicina de Precisão/tendências , Mutações Sintéticas Letais/efeitos dos fármacos
17.
J Chromatogr A ; 1531: 122-130, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29174572

RESUMO

Analysis and purification of boronic acid pinacol esters by RPLC is very challenging due to their degradation in aqueous and alcoholic solvents. These compounds are difficult to purify by SFC too as they are equally sensitive to traditional co-solvents like methanol, ethanol, and 2-propanol. 2,2,2 trifluoroethanol (TFE), which has been reported for the purification of a few alcohol sensitive compounds, was evaluated as a co-solvent in this study for the purification of chiral and achiral boronate esters by SFC. Examples of twelve compounds were presented in this paper where degradation of boronic acid pinacol esters was successfully controlled by replacing methanol with TFE as the co-solvent in SFC. A separate study showed that TFE can also control the epimerization of the enantiomers of 3 substituted 1,4 benzodiazepine analogues during the purification process. In addition to above benefits, 2,2,2trifloroethanol showed improved selectivity and resolution for most of the compounds. With its stronger solvent strength compared to other alcohols, TFE could also be used to reduce the co-solvent percentage needed for elution and to shorten retention time of highly polar samples which did not elute even in 50% of other co-solvents in SFC. A case study of compound B demonstrated that TFE provided a reduced co-solvent percentage and a shorter cycle time with much improved resolution as compared to methanol, thus resulting in higher loading and throughput with reduction of total solvent consumption.


Assuntos
Ácidos Borônicos/química , Cromatografia com Fluido Supercrítico/métodos , Ésteres/isolamento & purificação , Solventes/química , Trifluoretanol/química , Ésteres/química , Metanol/química , Estereoisomerismo
18.
J Med Chem ; 60(12): 5193-5208, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
19.
J Med Chem ; 60(9): 3795-3803, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28418664

RESUMO

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Quinazolinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cães , Espectrometria de Massas , Bloqueadores dos Canais de Potássio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
20.
Mater Sci Eng C Mater Biol Appl ; 75: 104-114, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28415387

RESUMO

This paper is focused on preparation and characterization of regenerated muga and tasar fibroin flexible films from cocoon using ionic liquid. These flexible muga and tasar fibroin films were prepared by incorporating dextrose (5 to 15% w/w) as plasticizer. The mechanical, thermal, physical, morphological and biological properties of dextrose plasticized muga and tasar fibroin films were characterized. These plasticized films showed higher elongation at break as well as water holding capacity as compared to the un-plasticized films. The surface roughness and water absorbance capacity of the dextrose plasticized films were higher than un-plasticized films, which results in improved adherence and proliferation of L929 fibroblast cells. Gentamicin loaded plasticized muga and tasar fibroin films showed slightly higher rate of release as compared to un-plasticized films. The biodegradability of dextrose plasticized films was significantly higher as compared to their respective counterpart. The regeneration of flexible muga and tasar silk fibroin films pave the way to expand potential use of non-mulberry in the field of biomedical such as wound dressing.


Assuntos
Bandagens , Fibroblastos , Fibroínas , Gentamicinas , Glucose , Membranas Artificiais , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Fibroínas/química , Fibroínas/farmacologia , Gentamicinas/química , Gentamicinas/farmacologia , Glucose/química , Glucose/farmacologia , Camundongos , Mariposas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA