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

doi:10.1021/acsmedchemlett.5b00070

. 2015 Apr 3;6(5):596-601.

doi: 10.1021/acsmedchemlett.5b00070. eCollection 2015 May 14.

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

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.

PMID: 26005540
PMCID: PMC4434474
DOI: 10.1021/acsmedchemlett.5b00070

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

Martin Pettersson et al. ACS Med Chem Lett. 2015.

. 2015 Apr 3;6(5):596-601.

doi: 10.1021/acsmedchemlett.5b00070. eCollection 2015 May 14.

Authors

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
PMCID: PMC4434474
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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

**Scheme 1. Evolution of the Pyridopyrazine-1,6-dione Series**

**Scheme 2. Synthesis of 9–13 and 15–21**

**Figure 1**
Guinea pig time course study.

**Scheme 3. Synthesis of 21**
Reagents and conditions: (a) 2-bromo-3,3,3-trifluoroprop-1-ene, (PPh₃)₂PdCl₂, K₂CO₃, THF, H₂O, rt, 70%; (b) BBr₃, CH₂Cl₂, −78 °C to rt, 74%; (c) 75 psi H₂, [RuCl(p-cymene)(S)-Segphos)]Cl, EtOH, 50 °C, 72%, 96% ee; (d) (S)-N-(t-butoxycarbonyl)alaninol methanesulfonate, Cs₂CO₃, DMF, 60 °C; (e) TFA, CH₂Cl₂, rt, then fumaric acid in MeOH, 78% (2 steps from 26); (f) 1,2-dibromoethane, Cs₂CO₃, DMF, 90 °C, 76%; (g) 27, DABAL-Me₃, THF, 70 °C, 72%; (h) TFAA (3.5 equiv), DBU (8 equiv), CH₃CN, 0 °C to rt, 85%.

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References

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1. Karran E.; Mercken M.; De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discovery 2011, 10, 698–712. - PubMed
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[1] Thies W.; Bleiler L. Alzheimer’s disease facts and figures. Alzheimers Dement. 2013, 9, 208–245. - PubMed

[2] Thies W.; Bleiler L. Alzheimer’s disease facts and figures. Alzheimers Dement. 2013, 9, 208–245. - PubMed

[3] Karran E.; Mercken M.; De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discovery 2011, 10, 698–712. - PubMed

[4] Karran E.; Mercken M.; De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discovery 2011, 10, 698–712. - PubMed

[5] Bateman R. J.; Siemers E. R.; Mawuenyega K. G.; Wen G.; Browning K. R.; Sigurdson W. C.; Yarasheski K. E.; Friedrich S. W.; Demattos R. B.; May P. C.; Paul S. M.; Holtzman D. M. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 2009, 66, 48–54. - PMC - PubMed

[6] Bateman R. J.; Siemers E. R.; Mawuenyega K. G.; Wen G.; Browning K. R.; Sigurdson W. C.; Yarasheski K. E.; Friedrich S. W.; Demattos R. B.; May P. C.; Paul S. M.; Holtzman D. M. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 2009, 66, 48–54. - PMC - PubMed

[7] De Strooper B. Lessons from a failed γ-secretase Alzheimer trial. Cell 2014, 159, 721–726. - PubMed

[8] De Strooper B. Lessons from a failed γ-secretase Alzheimer trial. Cell 2014, 159, 721–726. - PubMed

[9] Coric V.; van Dyck C. H.; Salloway S.; Andreasen N.; Brody M.; Richter R. W.; Soininen H.; Thein S.; Shiovitz T.; Pilcher G.; Colby S.; Rollin L.; Dockens R.; Pachai C.; Portelius E.; Andreasson U.; Blennow K.; Soares H.; Albright C.; Feldman H. H.; Berman R. M. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 2012, 69, 1430–1440. - PubMed

[10] Coric V.; van Dyck C. H.; Salloway S.; Andreasen N.; Brody M.; Richter R. W.; Soininen H.; Thein S.; Shiovitz T.; Pilcher G.; Colby S.; Rollin L.; Dockens R.; Pachai C.; Portelius E.; Andreasson U.; Blennow K.; Soares H.; Albright C.; Feldman H. H.; Berman R. M. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 2012, 69, 1430–1440. - PubMed

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

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

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