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

Basic Information

ID: ALA3997845

Journal: Bioorg Med Chem

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

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

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.

CiteXplore: 28279560

DOI: 10.1016/j.bmc.2017.02.045

Patent ID: ┄