Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders.
Structure-activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key compound 22 showed efficacy in a cuprizone-induced demyelination model with twice daily oral administration, thereby supporting CXCR2 to be a potential therapeutic target for the treatment of demyelinating diseases such as multiple sclerosis.
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences , 1 Xiannongtan Street, Beijing 100050, P. R. China.
Heng
H
Xu
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Hongfu
H
Lu
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Zhongmiao
Z
Xu
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Linbo
L
Luan
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Chengyong
C
Li
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Yan
Y
Xu
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Kelly
K
Dong
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Jinqiang
J
Zhang
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Xiong
X
Li
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Yvonne
Y
Li
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Gentao
G
Liu
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Sophie
S
Gong
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Yong-Gang
YG
Zhao
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Ailian
A
Liu
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Yueting
Y
Zhang
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Wei
W
Zhang
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Xin
X
Cai
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Jia-Ning
JN
Xiang
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
John D
JD
Elliott
Research and Development, GlaxoSmithKline , No. 3 Building, 898 Halei Road, Pudong, Shanghai 201203, P. R. China.
Xichen
X
Lin
CNS penetration; CXCR2 antagonists; cuprizone model; demyelinating disorders; demyelination and remyelination; diarylureas; multiple sclerosis