The prevalence of nonalcoholic steatohepatitis (NASH)
is increasing
rapidly worldwide, and NASH has become a serious problem for human
health. Recently, the selective activation of the intestinal farnesoid
X receptor (FXR) was considered as a more promising strategy for the
treatment of NASH with lesser side effects due to reduced systemic
exposure. Moreover, the inhibition of intestinal fatty acid binding
protein 1 (FABP1) alleviated obesity and NASH by reducing dietary
fatty acid uptake. In this study, the first-in-class intestinal restricted
FXR and FABP1 dual-target modulator ZLY28 was discovered by comprehensive
multiparameter optimization studies. The reduced systemic exposure
of ZLY28 might provide better safety by decreasing the on- and off-target
side effects in vivo. In NASH mice, ZLY28 exerted robust anti-NASH
effects by inhibiting FABP1 and activating the FXR-FGF15 signaling
pathway in the ileum. With the above attractive efficacy and preliminary
safety profiles, ZLY28 is worthy of further evaluation as a novel
anti-NASH agent.
Hyperuricemia has become a global problem and is one of the four basic metabolic diseases after hypertension, hyperlipidemia, and hyperglycemia. However, the existing drugs have undesired or serious adverse effects, such as the high risk of Stevens-Johnson syndrome for allopurinol, and the cardiovascular side effects induced by febuxostat. Therefore, it is an urgent need to develop an effective and safety agent for the treatment of hyperuricemia. The urate transporter 1 (URAT1) inhibitors have been considered as a promising uric acidlowering agents. To improve adverse reactions caused by excessive lipophilicity and large molecular weight of existing drugs, five novel low-molecular-weight URAT1 Inhibitors were designed and synthesized by molecular hybridisation. Among them, although compound 4 showed less potent activity than the classic URAT1 inhibitor benzbromarone in vitro, compound 4 exhibited better uric acid-lowering activity than benzbromarone in vivo, which may be related to the fact that compound 4 has lower lipophilicity than benzbromarone to facilitate drug absorption. In addition, compound 4 cherishes some merits, which have a smaller molecular weight and lower lipophilicity, and superior in vitro activity than lesinurad. Generally, the results indicate that compound 4, with a good therapeutic effect, is a prospective candidate for the treatment of hyperuricemia.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.