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This paper aims to develop and analyze the design method of multifocal contact lenses to obtain curvature continuity in the optical surfaces with the high addition (Add) powers by adjusting non-uniform rational B-spline (NURBS) curves. The paper has developed mathematical formulae to generate the optical power distributions in which the powers continuously change from either near or distant center to the opposite focal length in the periphery of the optical region with different change rates and Add power values. This developed method can efficiently adjust and optimize three parameters, including control points, weight, and knots of the NURBS, to be anterior optical lens surface profiles to adapt for these given power profiles. The result shows that the proposed contact lenses not only achieve smooth and continuous anterior optical surfaces, but also satisfy various optical power distributions with high Add power values for different pupil diameters. Then, these designs of contact lenses can be feasibly converted to the computer-aided design format for analysis and manufacture for molding or single-point diamond turning. Experimental results of this method have been tested and proven when both the power distributions of simulation of lenses and the actual machined samples match the original specified powers provided by clinical demands of a multifocal contact lens. Future integration with variant clinical demands and optimization rules of lens design can be explored for a progressive contact lens.
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Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.
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Tropanylamide was investigated as a possible scaffold for ß-tryptase inhibitors with a basic benzylamine P1 group and a substituted thiophene P4 group. Comparing to piperidinylamide, the tropanylamide scaffold is much more rigid, which presents less opportunity for the inhibitor to bind with off-target proteins, such as cytochrome P450, SSAO, and hERG potassium channel. The proposed binding mode was further confirmed by an in-house X-ray structure through co-crystallization.
Assuntos
Benzilaminas/química , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Tiofenos/química , Triptases/antagonistas & inibidores , Benzilaminas/farmacologia , Cristalografia por Raios X , Estabilidade de Medicamentos , Canal de Potássio ERG1 , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica/efeitos dos fármacos , Tiofenos/farmacologiaRESUMO
Classical high-throughput screening (HTS) technologies for the analysis of ionic currents across biological membranes can be performed using fluorescence-based, radioactive, and mass spectrometry (MS)-based uptake assays. These assays provide rapid results for pharmacological HTS, but the underlying, indirect analytical character of these assays can be linked to high false-positive hit rates. Thus, orthogonal and secondary assays using more biological target-based technologies are indispensable for further compound validation and optimization. Direct assay technologies for transporter proteins are electrophysiology-based, but are also complex, time-consuming, and not well applicable for automated profiling purposes. In contrast to conventional patch clamp systems, solid supported membrane (SSM)-based electrophysiology is a sensitive, membrane-based method for transporter analysis, and current technical developments target the demand for automated, accelerated, and sensitive assays for transporter-directed compound screening. In this study, the suitability of the SSM-based technique for pharmacological compound identification and optimization was evaluated performing cell-free SSM-based measurements with the electrogenic amino acid transporter B0AT1 (SLC6A19). Electrophysiological characterization of leucine-induced currents demonstrated that the observed signals were specific to B0AT1. Moreover, B0AT1-dependent responses were successfully inhibited using an established in-house tool compound. Evaluation of current stability and data reproducibility verified the robustness and reliability of the applied assay. Active compounds from primary screens of large compound libraries were validated, and false-positive hits were identified. These results clearly demonstrate the suitability of the SSM-based technique as a direct electrophysiological method for rapid and automated identification of small molecules that can inhibit B0AT1 activity.
Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Fenômenos Eletrofisiológicos , Ensaios de Triagem em Larga Escala/métodos , Sistemas de Transporte de Aminoácidos Neutros/agonistas , Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Animais , Bioensaio/métodos , Transporte Biológico/efeitos dos fármacos , Células CHO , Membrana Celular/metabolismo , Cricetulus , Humanos , Camundongos , Técnicas de Patch-Clamp/métodos , Reprodutibilidade dos Testes , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
A novel ß-tryptase inhibitor with a basic benzylamine P1 group, a piperidine-amide linker, and a substituted indole P4 group was discovered. A substitution at 4-indole position was introduced to constrain the conformational flexibility of the inhibitor to the bioactive conformation exhibited by X-ray structures so that entropic penalty was decreased. More importantly, this constrained conformation limited the accessibility of this molecule to anti-targets, especially SSAO, so that an enhanced metabolic profile was achieved.
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Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Triptases/antagonistas & inibidores , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Inibidores Enzimáticos/química , Humanos , Conformação Molecular , Simulação de Dinâmica Molecular , Difração de Raios XRESUMO
Colorectal cancer is a complex disease driven by well-established mutations such as APC and other yet to be identified pathways. The GTPase Rab11 regulates endosomal protein trafficking, and previously we showed that loss of Rab11 caused intestinal inflammation and hyperplasia in mice and flies. To test the idea that loss of Rab11 may promote cancer progression, we have analyzed archival human patient tissues and observed that 51 out of 70 colon cancer tissues had lower Rab11 protein staining. By using the Drosophila midgut model, we have found that loss of Rab11 can lead to three changes that may relate to cancer progression. First is the disruption of enterocyte polarity based on staining of the FERM domain protein Coracle. Second is an increased proliferation due to an increased expression of the JAK-STAT pathway ligand Upd3. Third is an increased expression of ImpL2, which is an IGFBP7 homolog and can suppress metabolism. Furthermore, loss of Rab11 can act synergistically with the oncoprotein RasV12 to regulate these cancer-related phenotypes.
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Neoplasias do Colo/genética , Proteínas de Drosophila/genética , Proteínas rab de Ligação ao GTP/genética , Animais , Polaridade Celular , Proliferação de Células , Neoplasias do Colo/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Enterócitos/citologia , Enterócitos/metabolismo , Enterócitos/fisiologia , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Difficult endotracheal intubation is a clinical challenge for anesthesiologists and other practitioners of airway management. The use of a tracheoscopic ventilation tube, a novel airway device, for endotracheal intubation during general anesthesia in two patients with difficult airways after unsuccessful direct laryngoscopy is presented.
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Manuseio das Vias Aéreas/métodos , Anestesia Geral/métodos , Intubação Intratraqueal/métodos , Adulto , Desenho de Equipamento , Feminino , Humanos , Intubação Intratraqueal/instrumentação , Laringoscopia/métodos , Pessoa de Meia-Idade , Respiração Artificial/instrumentaçãoRESUMO
A series of 4,5-diarylimidazoline libraries were prepared using high-throughput solid-phase and microwave techniques. The compounds were evaluated as P2X(7) antagonists and their SAR is described.