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Design, Synthesis, and Biological Evaluations of Several Fasudil Analogues
Author(s) -
Li Hang,
Zhou Xueyong,
Ye Hang,
Sun Xi,
Zhang Pingping
Publication year - 2019
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.3403
Subject(s) - pyrrolidine , chemistry , experimental autoimmune encephalomyelitis , encephalomyelitis , enantiomer , multiple sclerosis , fasudil , stereochemistry , autoimmune disease , hydroxymethyl , inhibitory postsynaptic potential , pharmacology , biochemistry , kinase , immunology , neuroscience , rho associated protein kinase , medicine , disease , biology
In our previous work, ( S )‐6 H ‐1‐(5‐isoquinolinesulfonyl)‐2‐hydroxymethyl‐1‐pyrrolidine and ( S )‐6 H ‐1‐(5‐isoquinolinesulfonyl)‐2‐chloromethyl‐1‐pyrrolidine displayed potent inhibitory activity. Therefore, with these two substances as lead compounds, we designed and synthesized their enantiomers to reveal the inhibitory effects of chirality on Rho kinase. It is found that their enantiomers exhibited much better Rho kinase inhibitory activity and strongly promoted synapse formation. Experimental autoimmune encephalomyelitis is a murine autoimmune disease used to study multiple sclerosis. With added antigens, the changes from C57BL/6 mice's limbs and tail was observed and scored by clinical evaluation. The synthetic compounds may simultaneously reduce symptoms of experimental autoimmune encephalomyelitis and inhibit inflammatory infiltration of the central nervous system. Thus, these compounds may be potential candidates for inhibition of Rho kinase and should be considered for further experimental study in relation to multiple sclerosis.