Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC 50 = 0.30 μM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R 1 ) and hydrophobic interactions of phenyl moiety (R 3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolonestype PL inhibitors for biomedical applications.
Doxophylline (DOXO) and theophylline are widely used as bronchodilators for treating asthma and chronic obstructive pulmonary disease, and DOXO has a better safety profile than theophylline. How DOXO metabolism and disposition affect its anti-asthmatic efficacy and safety remains to be explored. In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2) and etophylline (M4). A comparative analysis of DOXO metabolism in human using liver microsomes, S9 fraction, and plasma samples demonstrated that: (1) The metabolism of DOXO began with a CYP-mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 production was rather low. (2) M1 was further converted to M2 and M4, the end products of DOXO metabolism in vivo, by non-CYP dismutase in the cytosol. This dismutation process also relied on the ratio of NADP + /NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metabolism in human.
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