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  • br Conflict of interest br Acknowledgements The authors are


    Conflict of interest
    Acknowledgements The authors are grateful to laboratory technician Kristina Andersson for expert technical assistance. The authors acknowledge 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 primaquine phosphate 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.