Photoredox-based late-stage functionalization in SAR study for in vivo potent glucosylceramide synthase inhibitor

[Display omitted] Glucosylceramide synthase (GCS) has drawn much attention as an attractive protein target in the disease pathways of Parkinson’s Disease (PD) and lysosomal storage disorders, such as Gaucher’s Disease (GD). In previous our study, T-036 and its analogue, 2a, were discovered as novel...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2022-12, Vol.77, p.129039-129039, Article 129039
Main Authors: Wang, Junsi, Reynolds, Matthew, Ibáñez, Ignacio, Sasaki, Yusuke, Tanaka, Yuta, Kikuchi, Fumiaki, Ohashi, Tomohiro, Sato, Sho, Miyabayashi, Mariko, Fujii, Takahiro
Format: Article
Language:English
Subjects:
Gaucher Disease - metabolism
Glucosylceramide synthase
Glucosyltransferases
Humans
Late-stage functionalization
Parkinson Disease
Photoredox
Structure–activity relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] Glucosylceramide synthase (GCS) has drawn much attention as an attractive protein target in the disease pathways of Parkinson’s Disease (PD) and lysosomal storage disorders, such as Gaucher’s Disease (GD). In previous our study, T-036 and its analogue, 2a, were discovered as novel GCS inhibitors. To further improve activity of this chemical series, SAR was investigated on the fused pyridyl ring core of 2a by employing a photoredox reaction that significantly reduced synthetic demand. Herein, we successfully applied the decarboxylation C–H alkylation photoredox reaction to introduce a wide variety of substituents at the 6-position of the fused pyridine core scaffold. This quick SAR acquisition facilitated the swift identification of the potent GCS inhibitors 2b (IC50 = 5.9 nM) and 2g (IC50 = 3.6 nM). Moreover, 2b exhibited superior in vivo potency to that of our previously reported lead compound, T-036.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.129039