Alogliptin is a potent selective inhibitor of the serine

Alogliptin is a potent, selective inhibitor of the serine protease DPP-4 [10]. Alogliptin or (2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl] benzonitrile) (C, Fig. 2), a potent (IC50 < 10 nM) and selective inhibitor (selectivity > 10,000 over DPP-8 and 9) was identified by replacing the quinazolinone moiety of another inhibitor D with a pyrimidine dione [11]. We have designed N-benzylated (B, Fig. 2) and N-methylated pyrimidine diones (A, Fig. 2) by taking Alogliptin (C) and Quinazoline scaffold (D) as reference moieties.
Materials and methods
Result and discussion The peptidase activity of the enzyme has been evaluated in the enzymatic assay. Some compounds had shown inhibitory activity in significant range (3c, 3d, 3e, 5c). Few other compounds (3a, 5d) have demonstrated DPP-4 inhibition in moderate range (Table 3). Val pro was taken as standard for the assay which has 33.05% of DPP-4 inhibitory activity.
Conclusion From the series of synthesized N-methylated and N-benzylated pyrimidinediones, it may be concluded that the presence of NVP-BSK805 synthesis rich species with pyrimidinediones is vital for enhancing binding with target, although, incorporation of steric bulky group must be taken into consideration, which may alter DPP-4 inhibitory activity. The presence of electron withdrawing group has lowered DPP-4 inhibitory activity (like Cl in Compound 3b). Inclusion of bicyclic or tricyclic moieties may favour a strong π-π stacking interaction. N-methylated pyrimidinediones can further be optimized to N-ethylated, N-propylated and so on, that could be an interesting derivatisation to explore further. Presence of CF3 has been contrary with respect to CN and appears to be a key factor in pharmacological activity of N-benzylated compounds. Through comparative molecular docking studies of synthesized potent Compounds (3a, 3c 3d, 3e, 5c and 5d) with some natural DPP-4 inhibitors (Diprotin A, Flavone, Quercetin, Resveratrol), it has led to a conclusion that there are some important amino acid interactions in DPP-4 subunit through Tyr 666, Tyr 662, Arg 125, Glu 206 etc, which are identical in both synthesized compounds as well as natural DPP-4 inhibitor This kind of similarity rationalizes that synthesized compounds possesses important key features like 3D-conformation, physicochemical property like natural DPP-4 inhibitors, which directly corresponds to DPP-4 inhibitory activity against diabetes.
Conflict of interest
Acknowledgements
Introduction Glucocorticoids (GCs) are the most effective anti-inflammatory and immunosuppressive agents for the treatment of severe inflammatory diseases such as asthma and rheumatoid arthritis (Schäcke et al., 2002). Several reports have shown that excess endogenous and exogenous GC exposure has been associated with the development of glucose deregulation such as glucose intolerance, insulin resistance (IR), hyperglycemia and eventually diabetes mellitus in both (Hoes et al., 2011; Di Dalmazi et al., 2012; Rafacho et al., 2014; Pasieka and Rafacho, 2016).