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.
Nylon 6 extract concentrate, namely, wastewater produced from industrial nylon 6 extraction unit, was hydrolyzed in subcritical water to efficiently decrease the cyclic dimer (CD) content. The CD equilibrium conversion reached a maximum when the initial water content ranged from 0.40 to 0.45 g/g; specifically, a CD conversion of 94.3 % was achieved at the hydrolysis temperature of 543 K and an initial water content of 0.40 g/g. A kinetic model including both acid‐ and base‐catalyzed mechanisms was developed. The model predictions were in good agreement with the experimental results. The hydrolysis reaction constants increased significantly with increasing subcritical water content. By considering the effects of subcritical water on the individual reaction constants, the kinetic model could reproduce the experimental results over a wide range of initial water contents. Hopefully, the developed kinetic model will be applied in the design of a novel nylon 6 extract liquor recycling process.
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