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Fluorinated piperidine acetic acids as gamma-secretase modulators. 2010
Matthew G Stanton, and
Jed Hubbs, and
David Sloman, and
Christopher Hamblett, and
Paula Andrade, and
Minilik Angagaw, and
Grace Bi, and
Regina M Black, and
Jamie Crispino, and
Jonathan C Cruz, and
Eric Fan, and
Georgia Farris, and
Bethany L Hughes, and
Candia M Kenific, and
Richard E Middleton, and
George Nikov, and
Peter Sajonz, and
Sanjiv Shah, and
Nirah Shomer, and
Alexander A Szewczak, and
Flobert Tanga, and
Matthew T Tudge, and
Mark Shearman, and
Benito Munoz
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. matthew_stanton@merck.com
We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.
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