Lesinurad, a human urate transporter
1 (URAT1) inhibitor approved
as a medication for the treatment of hyperuricemia associated with
gout in 2015, can cause liver and renal toxicity. Here, we modified
all three structural components of lesinurad by applying scaffold
hopping, bioisosterism, and substituent-decorating strategies. In
a mouse model of acute hyperuricemia, 21 of the synthesized compounds
showed increased serum uric acid (SUA)-reducing activity; SUA was
about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone.
In the URAT1 inhibition assay, 44 was over 8-fold more
potent than lesinurad (IC50: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent
inhibitory activity (IC50 = 31.73 μM) against GLUT9.
Furthermore, we also preliminarily explored the effect of chirality
on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear
to be promising candidates for the treatment of hyperuricemia and
gout.
Lesinurad is a uricosuric agent for
the treatment of hyperuricemia
associated with gout, which was found lacking in efficacy and safety.
Here, scaffold hopping and molecular hybridization were exploited
to modify all the structural components of lesinurad, and 36 novel
compounds bearing bicyclic imidazolopyridine core were obtained. In
a mouse model of acute hyperuricemia, 29 compounds demonstrated increased
serum uric acid (SUA)-reducing activity; SUA was treated with 12, 23, and 29 about fourfold lower
compared with that of lesinurad. Moreover, 23 exhibited
stronger URAT1 inhibition activity (IC50 = 1.36 μM)
than lesinurad (IC50 = 5.54 μM). Additionally, 23 showed favorable safety profiles, and no obvious acute
toxicity was observed in Kunming mice under a single dose of 1000
mg·kg–1. 23 also achieved excellent
pharmacokinetic properties with the oral bioavailability of 59.3%.
Overall, all the results indicated that 23 is a promising
drug candidate in the treatment of hyperuricemia and gout.
With our continuous endeavors in seeking neuraminidase
(NA) inhibitors,
we reported herein three series of novel oseltamivir amino derivatives
with the goal of exploring the druggable chemical space inside the
150-cavity of influenza virus NAs. Among them, around half of the
compounds in series C were demonstrated to be better
inhibitors against both wild-type and oseltamivir-resistant group-1
NAs than oseltamivir carboxylate (OSC). Notably, compounds 12d, 12e, 15e, and 15i showed
more potent or equipotent antiviral activity against H1N1, H5N1, and
H5N8 viruses compared to OSC in cellular assays. Furthermore, compounds 12e and 15e exhibited high metabolic stability
in human liver microsomes (HLMs) and low inhibitory effect on main
cytochrome P450 (CYP) enzymes, as well as low acute/subacute toxicity
and certain antiviral efficacy in vivo. Also, pharmacokinetic
(PK) and molecular docking studies were performed. Overall, 12e and 15e possess great potential to serve
as anti-influenza candidates and are worthy of further investigation.
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