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Shanghai, China

Park H.-K.,University of Ulsan | Jo W.,University of Ulsan | Choi H.-J.,University of Ulsan | Kim B.,University of Ulsan | And 9 more authors.
Journal of Applied Toxicology | Year: 2015

Many systemic drugs can induce ocular toxicity and several ocular side-effects have been identified in clinical studies. However, it is difficult to detect ocular toxicity in preclinical studies because of the lack of appropriate evaluation methods. Optical coherence tomography (OCT) is useful because it can provide real-time images throughout a study period, whereas histopathology only provides images of sacrificed animals. Using OCT alongside histopathology, attempts were made to find effective approaches for screening of drug-induced ocular toxicity in monkeys. Such approaches could be used in preclinical studies prior to human trials. Six male cynomolgus monkeys (Macaca fascicularis Raffles) were orally administered one of six candidate MAPK/ERK kinase (MEK) inhibitors. Central serous chorioretinopathy, a known side-effect of such inhibitors, was identified in four monkeys by OCT. Artifacts generated during tissue processing meant that histopathology could not detect edematous changes. Thus, OCT is a useful tool to detect ocular toxicity which cannot be detected by histopathology in preclinical studies. © 2014 John Wiley & Sons, Ltd.

Le P.T.,Pfizer | Richardson P.F.,Pfizer | Sach N.W.,Pfizer | Xin S.,WuXi Applied Tec Co. | And 3 more authors.
Organic Process Research and Development | Year: 2015

A robust process for the preparation of multigram quantities of 4-aminopyrimidin-5-ol (5) in good yield from an inexpensive and readily available pyrimidine starting material is described. An initial evaluation of the reported literature route for this material utilizing a de novo pyrimidine synthesis provided safety concerns over the scalability of several intermediates. In addition, a number of steps proceeded in mediocre yield, and involved chromatographic separations for the desired products. The newly developed route mitigates the safety concerns, reduces the number of steps from five to three, avoids column chromatography, leads to an 8-fold improvement in yield, and utilizes reagents, which are recognized to be more environmentally benign. © 2015 American Chemical Society.

Scales S.,Pfizer | Johnson S.,Pfizer | Hu Q.,Pfizer | Do Q.-Q.,Pfizer | And 11 more authors.
Organic Letters | Year: 2013

Differences in regioselectivity were observed during the SNAr reaction of amines with unsymmetrical 3,5-dichloropyrazines. This study revealed that when the 2-position of the pyrazine was occupied with an electron-withdrawing group (EWG), nucleophilic attack occurred preferentially at the 5-position. When the 2-position was substituted with an electron-donating group (EDG), nucleophilic attack occurred preferentially at the 3-position. These results are reported along with a computational rationale for the experimental observations based on the Fukui index at the reacting centers. © 2013 American Chemical Society.

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