Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability

ACS Med Chem Lett. 2015 Apr 3;6(5):596-601. doi: 10.1021/acsmedchemlett.5b00070.

Martin Pettersson ¹, Douglas S Johnson ¹, John M Humphrey ², Todd W Butler ², Christopher W Am Ende ², Benjamin A Fish ², Michael E Green ¹, Gregory W Kauffman ², Patrick B Mullins ², Christopher J O'Donnell ², Antonia F Stepan ¹, Cory M Stiff ², Chakrapani Subramanyam ², Tuan P Tran ², Beth Cooper Vetelino ², Eddie Yang ², Longfei Xie ², Kelly R Bales ¹, Leslie R Pustilnik ², Stefanus J Steyn ¹, Kathleen M Wood ¹, Patrick R Verhoest ¹

Affiliations

1 Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
2 Pfizer Worldwide Research & Development , Eastern Point Road, Groton, Connecticut 06340, United States.

PMID: 26005540 DOI: 10.1021/acsmedchemlett.5b00070

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.

Keywords

Alzheimer’s disease; LipMetE; fluorine; gamma secretase modulators; lipophilic metabolism efficiency.

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