Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors.

Abstract:

:In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.

journal_name

J Med Chem

authors

Zhao Z,Pissarnitski DA,Josien HB,Wu WL,Xu R,Li H,Clader JW,Burnett DA,Terracina G,Hyde L,Lee J,Song L,Zhang L,Parker EM

doi

10.1021/acs.jmedchem.5b00774

subject

Has Abstract

pub_date

2015-11-25 00:00:00

pages

8806-17

issue

22

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章