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

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

doi:10.1021/acsmedchemlett.5b00070

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. eCollection 2015 May 14.

Authors

Martin Pettersson¹, Douglas S Johnson¹, John M Humphrey², Todd W Butler², Christopher W Am Ende², Benjamin A Fish², Michael E Green¹, Gregory W Kauffman², Patrick B Mullins², Christopher J O'Donnell², Antonia F Stepan¹, Cory M Stiff², Chakrapani Subramanyam², Tuan P Tran², Beth Cooper Vetelino², Eddie Yang², Longfei Xie², Kelly R Bales¹, Leslie R Pustilnik², Stefanus J Steyn¹, Kathleen M Wood¹, Patrick R Verhoest¹

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.

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.