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Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors.

Abstract：

:Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1mg/kg.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Yamaki S,Suzuki D,Fujiyasu J,Neya M,Nagashima A,Kondo M,Akabane T,Kadono K,Moritomo A,Yoshihara K

doi

10.1016/j.bmc.2016.10.025

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

187-201

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)31035-5

journal_volume

25

pub_type

杂志文章

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