Bisphosphonate ester
2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds
6e, 6i, 6j, and
6m, ...which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.
Bisphosphonate ethyl and cyclic ester derivatives have been synthesized through a Michael-like addition to a vinylidene bisphosphonate. Many, including compound
6m, demonstrated inhibition of animal models of inflammation and arthritis.
The discovery and optimization of a series of 6,7-dihydro-5H-cyclopentadpyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and ...optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase–Akt–mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to ...stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.
Cholangiocarcinoma (CCA) presents significant diagnostic challenges, resulting in late patient diagnosis and poor survival rates. Primary sclerosing cholangitis (PSC) patients pose a particularly ...difficult clinical dilemma because they harbor chronic biliary strictures that are difficult to distinguish from CCA. MicroRNAs (miRs) have recently emerged as a valuable class of diagnostic markers; however, thus far, neither extracellular vesicles (EVs) nor miRs within EVs have been investigated in human bile. We aimed to comprehensively characterize human biliary EVs, including their miR content. We have established the presence of extracellular vesicles in human bile. In addition, we have demonstrated that human biliary EVs contain abundant miR species, which are stable and therefore amenable to the development of disease marker panels. Furthermore, we have characterized the protein content, size, numbers, and size distribution of human biliary EVs. Utilizing multivariate organization of combinatorial alterations (MOCA), we defined a novel biliary vesicle miR‐based panel for CCA diagnosis that demonstrated a sensitivity of 67% and specificity of 96%. Importantly, our control group contained 13 PSC patients, 16 with biliary obstruction of varying etiologies (including benign biliary stricture, papillary stenosis, choledocholithiasis, extrinsic compression from pancreatic cysts, and cholangitis), and 3 with bile leak syndromes. Clinically, these types of patients present with a biliary obstructive clinical picture that could be confused with CCA. Conclusion: These findings establish the importance of using extracellular vesicles, rather than whole bile, for developing miR‐based disease markers in bile. Finally, we report on the development of a novel bile‐based CCA diagnostic panel that is stable, reproducible, and has potential clinical utility. (Hepatology 2014;60:896–907)
We describe the use of optical coherence tomography (OCT) for high-resolution, real-time imaging of three-dimensional structure and development of a
biofilm in a standard capillary flow-cell model. ...As the penetration depth of OCT can reach several millimeters in scattering samples, we are able to observe complete biofilm development on all surfaces of a
flow-cell. We find that biofilm growing at the bottom of the tube has more structural features including voids, outward projections, and microcolonies while the biofilm growing on the top of the tube is relatively flat and contains less structural features. Volume-rendered reconstructions of cross-sectional OCT images also reveal three-dimensional structural information. These three-dimensional OCT images are visually similar to biofilm images obtained with confocal laser scanning microscopy, but are obtained at greater depths. Based on the imaging capabilities of OCT and the biofilm imaging data obtained, OCT has potential to be used as a non-invasive, label-free, real-time,
and/or
imaging modality for biofilm characterization.
A large-aperture, electromagnetic model for coherent microscopy is presented and the inverse scattering problem is solved. Approximations to the model are developed for near-focus and far-from-focus ...operations. These approximations result in an image-reconstruction algorithm consistent with interferometric synthetic aperture microscopy (ISAM): this validates ISAM processing of optical-coherence-tomography and optical-coherence-microscopy data in a vectorial setting. Numerical simulations confirm that diffraction-limited resolution can be achieved outside the focal plane and that depth of focus is limited only by measurement noise and/or detector dynamic range. Furthermore, the model presented is suitable for the quantitative study of polarimetric coherent microscopy systems operating within the first Born approximation.
The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups ...explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.
Virtual and high-throughput screening identified imidazo1,2-
apyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo2,3-
cpyridine ...indanone oximes as highly potent and selective inhibitors of B-Raf.
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