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Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation.

Abstract：

:Hormone sensitive lipase (HSL) has emerged as an attractive target for the treatment of dyslipidemia. We previously reported compound 1 as a potent and orally active HSL inhibitor. Although an attractive profile was demonstrated, subsequent studies revealed that compound 1 has a bioactivation liability. The oxygen-carbon linker in compound 1 was identified as being potentially responsible for reactive metabolite formation. By exchanging of this susceptible fragment was feasible, and a benzanilide derivative 6b with a decreased bioactivation liability was obtained. Further modification of the novel benzanilide scaffold resulted in the identification of compound 24b. Compound 24b exhibited potent HSL inhibitory activity (IC50=2nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3mg/kg.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Ogiyama T,Yamaguchi M,Kurikawa N,Honzumi S,Yamamoto Y,Sugiyama D,Takakusa H,Inoue SI

doi

10.1016/j.bmc.2017.02.045

subject

Has Abstract

pub_date

2017-04-01 00:00:00

pages

2234-2243

issue

7

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(17)30051-2

journal_volume

25

pub_type

杂志文章

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