Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.
Poor medication adherence
is one of the leading causes of suboptimal
glycaemic control in approximately half of the patients with type
2 diabetes mellitus (T2DM). Long-acting antidiabetic drugs are clinically
needed for improving patients’ compliance. Dipeptidyl peptidase-4
(DPP-4) inhibitors play an increasingly important role in the treatment
of T2DM because of their favorable properties of weight neutrality
and hypoglycemia avoidance. Herein, we report the successful discovery
and scale-up synthesis of compound 5, a structurally
novel, potent, and long-acting DPP-4 inhibitor for the once-weekly
treatment of T2DM. Inhibitor 5 has fast-associating and
slow-dissociating binding kinetics profiles as well as slow clearance
rate and long terminal half-life pharmacokinetic properties. A single-dose
oral administration of 5 (3 mg/kg) inhibited >80%
of
DPP-4 activity for more than 7 days in diabetic mice. The long-term
antidiabetic efficacies of 5 (10 mg/kg, qw) were better
than those of the once-weekly trelagliptin and omarigliptin, especially
in decreasing the hemoglobin A1c level.
UbcH5c belongs to the ubiquitin-conjugating enzyme family and plays an important role in catalyzing ubiquitination during TNF-α--triggered NF-κB activation. Therefore, UbcH5c is a potent therapeutic target for the treatment of inflammatory and autoimmune diseases induced by aberrant activation of NF-κB. In this study, we established a stable expression system for recombinant UbcH5c and solved the crystal structure of UbcH5c belonging to space group P22121 with one molecule in the asymmetric unit. This study provides the basis for further study of UbcH5c including the design of UbcH5c inhibitors.
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