Abstract:
:Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aβ42 and Aβ40 were observed in a guinea pig time-course experiment.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Pettersson M,Johnson DS,Humphrey JM,Butler TW,Am Ende CW,Fish BA,Green ME,Kauffman GW,Mullins PB,O'Donnell CJ,Stepan AF,Stiff CM,Subramanyam C,Tran TP,Vetelino BC,Yang E,Xie L,Bales KR,Pustilnik LR,Steyn SJ,Wood Kdoi
10.1021/acsmedchemlett.5b00070subject
Has Abstractpub_date
2015-04-03 00:00:00pages
596-601issue
5issn
1948-5875journal_volume
6pub_type
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