Format

Send to

Choose Destination
Bioorg Med Chem. 2018 Dec 21. pii: S0968-0896(18)31630-4. doi: 10.1016/j.bmc.2018.12.026. [Epub ahead of print]

Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo.

Author information

1
Respiratory Stress and Repair DPU, GlaxoSmithKline, Upper Providence, PA 19426, USA. Electronic address: jeffrey.c.boehm@gsk.com.
2
Respiratory Stress and Repair DPU, GlaxoSmithKline, Upper Providence, PA 19426, USA.
3
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK.
4
Platform Technology and Science, GlaxoSmithKline, Upper Providence, PA 19426, USA.

Abstract

The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.

KEYWORDS:

COPD; Isothiocyanate; KEAP1; Nrf2; Sulforaphane

PMID:
30626555
DOI:
10.1016/j.bmc.2018.12.026

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center