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  • The synthesis of compounds a and b are outlined


    The synthesis of compounds 7a and 7b are outlined in Scheme 2. Compound 5 was obtained by di-tert-butyl pyrocarbonate protection of IT-901 4a. Then, compounds 6a and 6b were obtained by amination of the fluoride with a morpholino and dimethylamine, respectively. Target compounds 7a and 7b were obtained by de-protection of compounds 6a and 6b with an HCl/MeOH solution. Scheme 3 introduced the synthesis of compounds 9a-f. Compound 3a was converted to compounds 8a-b by bromination with N-bromosuccinimide (NBS), to compounds 8c-d by fluorination with selectfluor, and to compounds 8e and 8f by sulphonation and N-alkylation with methanesulfonyl chloride and 2-(bromomethyl)-4-fluorobenzonitrile, respectively. Desired compounds 9a-f were obtained through amination of the chloro-precursors of 8a-f with 3-(R)-aminopiperidine. The synthesis of compounds 12a-j, which is shown in Scheme 4, was similar with other named compounds above. Compounds 11a-j were obtained by Suzuki reaction with various phenylboric acids and the bromide form of compound 10, which was obtained by protection of compound 9a with di-tert-butyl pyrocarbonate. The final compounds 12a-j were obtained by de-protection of compounds 11a-j with HCl/MeOH solution.
    Results and discussion
    Conclusion In the continuation of our discovery of long-acting DPP-4 inhibitors, a previously reported pyrrolopyrimidine scaffold-based compound (Fig. 2) was chosen to be the hit compound due to its pharmacokinetic superiority. Inspired by the discovery of trelagliptin, tentative variations on the pyrrole ring gave the lead compound 4a (IC50 = 2.3 nM, t1/2(rat) = 5.46 h). Extensive lead optimization was conducted by considering the binding mode between xanthine-based compounds and DPP-4. β-Substitution of the pyrrole ring was determined to be a good position for wild variation. Meanwhile, the excellent DPP-4 inhibitory activity was maintained by the β-substitution, as represented by compound 12a (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). The in vivo pharmacodynamics study demonstrated similar or slightly better sustained efficacy compared with trelagliptin. By reviewing the development course, the improved pharmacokinetics profile was important for prolonging the efficacy of the pyrrolopyrimidine- or xanthine-based DPP-4 inhibitors, especially the half-life. The strong affinity and in vivo inhibition at later time points against DPP-4 might have also contributed. Based on these preliminary data, compounds 4a and 12a will undergo more comprehensive evaluations in the due course, and in depth dose-response relationship research will be performed to evaluate the nature of these compounds.
    Experimental section
    Acknowledgements This research was supported by the National Natural Science Foundation of China (81402795) and a Grant from the Bureau of Education of Guangzhou Municipality (1201630308).
    Introduction Diabetes mellitus is a serious worldwide health problem. The higher prevalence of diabetes seen in recent decades increases the risk of serious diabetes complications. Diabetic retinopathy is one of the major complications of diabetes and the main cause of diabetes-related blindness [1]. It has been estimated that approximately one third of diabetes patients have signs of retinopathy and many of them have vision-threatening risk factors [2]. The retina is a specialized tissue that converts visible light into the neuronal signals which are perceived by the brain. The retina's unique vascular system provides nutrients and oxygen to the inner and outer retina, the integrity of which is essential for sensing light. The retinal vascular structure has features similar to the blood brain barrier and is highly sensitive to the microenvironment. Upon prolonged exposure to chronic hyperglycemia conditions, retinal endothelial cells undergo a range of unique structural changes, such as altered permeability, hyper-proliferation of endothelial cells and edema, and abnormal vascularization of the retina, resulting in loss of vision. Extensive studies have demonstrated that oxidative stress and inflammation are linked to one another and act as significant drivers of these diabetic complications. Recent research has been focused on specific mechanism-based strategies to target both oxidative stress and inflammatory pathways, thereby improving the complication burden of diabetes patients, including retinopathy [3]. Often the early stages of diabetic retinopathy have no visual symptoms, so early detection and treatment is of utmost importance in preventing significant vision loss from diabetic retinopathy. It has been proposed that an efficient early medical treatment would be significant in preventing further vision loss due to diabetic retinopathy.