Peroxisome proliferator-activator
receptors α/δ (PPARα/δ)
are regarded as potential therapeutic targets for nonalcoholic steatohepatitis
(NASH). However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial,
probably due to its weak PPARα/δ agonistic activity and
poor metabolic stability. Other reported PPARα/δ dual
agonists either exhibited limited potency or had unbalanced PPARα/δ
agonistic activity. Herein, we report a series of novel triazolone
derivatives as PPARα/δ dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARα/δ
agonistic activity (PPARα EC50 = 7.0 nM; PPARδ
EC50 = 8.4 nM) and a high selectivity over PPARγ
(PPARγ EC50 = 1316.1 nM) in PPAR transactivation
assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-agonist interaction. H11, which had excellent PK properties and a good safety profile,
showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or other inflammatory
and fibrotic diseases.
USP7 emerges as a potential therapeutic target for cancers,
as
it plays an important role in the development of tumorigenesis by
stabilizing multiple cancer-relevant proteins. Nevertheless, the discovery
of drug-like USP7 inhibitors remains challenging. Herein, we report
a series of N-benzylpiperidinol derivatives as potent
and selective USP7 inhibitors (e.g., X20 and X26: IC50 = 7.6 and 8.2 nM), whose binding modes were revealed
by crystallographic studies to be distinct from the known N-acylpiperidinol USP7 inhibitors. Among them, X36 with good oral PK profiles (rat: F = 40.8% and T
1/2 = 3.5 h) exhibited significant antitumor
efficacy in the MC38 colon cancer syngeneic mouse model, at least
partly through upregulating the tumor infiltration of CD8+ T, NK, and NKT cells and downregulating that of Tregs and MDSCs.
These findings may further pave the way for the development of USP7
inhibitors as novel cancer immunotherapy drugs.
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