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West Point, PA, United States

Stanton M.G.,Merck And Co. | Hubbs J.,Merck And Co. | Sloman D.,Merck And Co. | Hamblett C.,Merck And Co. | And 18 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor®. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Aβ42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250 mg/kg per day, AUC0-24 = 2100 μM h) did not exhibit Notch-related effects. © 2009 Elsevier Ltd. All rights reserved. Source

He S.,Merck And Co. | Lai Z.,Merck And Co. | Ye Z.,Merck And Co. | Dobbelaar P.H.,Merck And Co. | And 35 more authors.
ACS Medicinal Chemistry Letters | Year: 2014

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress. © 2014 American Chemical Society. Source

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