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  • A 205804 br Conflict of interest br Acknowledgements The aut


    Conflict of interest
    Acknowledgements The authors are grateful to laboratory technician Kristina Andersson for expert technical assistance. The authors acknowledge A 205804 the Swedish Research Council (Grant no. 6834), Region Skåne and Faculty of Medicine, Lund University, for financial support.
    Introduction Diabetes mellitus is a chronic metabolic disease characterized by hyperglycaemia that has reached a world prevalence of 415 million patients. Moreover, this population is expected to rise rapidly to 642 million by 2040. Type 2 diabetes (T2D), which accounts for up to 90% of diabetes patients, is due to an insufficient response to insulin [1]. Undiagnosed T2D and the multisystem complications caused by hyperglycaemia are the leading reason for patients\' disability and mortality. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a type of weight-neutral and well-tolerated glucose-lowering agents that dominantly function by inhibiting the cleavage of glucagon-like peptide-1 (GLP-1). GLP-1, an important incretin hormone, has multiple glucose regulation functions including stimulating insulin release in a glucose-dependent manner, increasing the sensitivity of insulin, and reducing A 205804 secretion [2], [3]. Currently, DPP-4 inhibitors are recommended as an add-on therapy with metformin or as the first-line therapy in patients with metformin contraindications [4]. However, despite the many available drugs, poor adherence has led to unsatisfying glycaemic control in approximately half of T2D patients [5]. Combination treatments and a reduction in the dosing frequency are common strategies to improve patient adherence [6]. Thus, long-acting glucose-lowering agents have been marketed successively, including once-weekly DPP-4 inhibitors. Trelagliptin and omarigliptin were the first two long-acting DPP-4 inhibitors that received marketing authorization in Japan in 2015 (Fig. 1) [7], [8]. Clinical trials data for these two drugs demonstrated their superior efficacy compared to the placebo and that they were not associated with any severe adverse events [9]. Compared to regular DPP-4 inhibitors, once-weekly trelagliptin and omarigliptin did not show significantly better efficacy in terms of glycaemic control [10], [11], and omarigliptin was reported to be linked with potential safety issues [12]; thus, both manufacturers abandoned their marketing plans in other countries with the consideration of high financial costs [9]. Nonetheless, long-acting DPP-4 inhibitors are needed due to the fast escalation of T2D patients, to provide more choices for therapeutic drug treatments regardless of concerns [13]. Previously, we reported a series of pyrrolopyrimine analogues based on pharmacokinetic (PK) property-driven optimization. The basal scaffold is represented by the hit compound in Fig. 2[14]. In our continuous drug discovery effort for potent oral DPP-4 inhibitors with long-acting properties, we started from the pyrrolopyrimine scaffold, which bears a fine PK profile. Inspired by the discovery of trelagliptin, a 5-floro substitution was simply added to the cyanobenzyl group to generate the lead compound 4a (IC50 = 2.3 nM), which displayed a similar half-life to trelagliptin in rat PK experiments. An additional structure-activity relationship (SAR) study was performed around compound 4a and indicated that pyrrole ring β-substitution improved DPP-4 affinity and was open to wide variations. Eventually the thienyl substituted compound 12a was proven to demonstrate sustained in vivo DPP-4 inhibition in pharmacodynamics (PD) assays, which was similar to or slightly better than trelagliptin.
    Chemistry The synthesis of compounds 4a-d is outlined in Scheme 1. Hydrolization of compounds 1a-d with aqueous sodium hydroxide gave compounds 2a-d. Protection of compounds 2a-d with di-tert-butyl pyrocarbonate produced compounds 2a’-b’. Selective N-alkylation of compounds 2a’-b’ and 2c-d with 2-(bromomethyl)-4-fluorobenzonitrile provided precursor compounds 3a-d. The final compounds 4a-d were obtained by amination of the chloro-precursors 3a-d with 3-(R)-aminopiperidine.