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

Publication date: Available online 27 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Tomoko Ogiyama, Mitsuhiro Yamaguchi, Nobuya Kurikawa, Shoko Honzumi, Yamamoto Yuka, Daisuke Sugiyama, Hideo Takakusa, Shinichi Inoue
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 = 2 nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3 mg/kg.

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