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ACS Medicinal Chemistry Letters
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3.74
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2453
Papers 2479
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The concepts behind targeting waters for potency and selectivity gains have been well documented and explored, although maximizing such potential gains can prove to be challenging. This problem is exacerbated in cases where there are multiple interacting waters, wherein perturbation of one water can affect the free energy landscape of the remaining waters. Knowing the right modification a priori is challenging, and computational approaches are ideally suited to help answer the key question of wh...
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Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane 2c, 3c and quinoline 2d, 3d-substituted diazepane derivatives, which showed the h...
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Here we report the nanomolar potencies of N1, N3-dialkyldioxonaphthoimidazoliums against asexual forms of sensitive and resistant Plasmodium falciparum. Activity was dependent on the presence of the fused quinone-imidazolium entity and lipophilicity imparted by the N1/ N3 alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC50 < 1 µM. A representative analog with good solubility, limited PAMPA permeability and microsomal stability, demonstrate...
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The identification and lead optimization of a series of pyrazolo[3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.
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Chidamide is a histone deacetylase (HDAC) inhibitor, which is currently used to treat cutaneous T-cell lymphoma in clinic. Herein nicotinamide phosphoribosyltransferase (NAMPT) was identified to be a new target of chidamide on the basis of the pharmacophore analysis, molecular docking, biological assays, inhibitor design and structure-activity relationship study. The polypharmacology of chidamide will provide important information for better understanding its antitumor mechanism. Also, design of...
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The HDAC inhibitor 4-(tert-butyl)-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising pre-clinical candidate for the treatment of acute myeloid leukemia (AML); an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic w...
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In-line purification is an important tool for flow chemistry. It enables an effective handling of unstable intermediates and an integration of multiple synthetic steps. Such integrated flow synthesis is useful for drug synthesis and process development in medicinal chemistry. In this article, we overview current states of in-line purification methods. In particular, we focus on four common methods: scavenger column, distillation, nanofiltration, and extraction. Examples of their applications are...
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The importance of physicochemical property calculation and measurement is well established in drug discovery. In particular, lipophilicity predictions play a central role in target design and prioritization. While significant progress has been made in our ability to calculate both logP and logD, the quality of these predictions is limited by the size and diversity of the underlying data set. Access to diverse datasets and advanced models is often limited to large organizations or consortia, and ...
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