GPR119 agonists for the treatment of type 2 diabetes

Abstract

GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels in vivo. As a stand-alone therapy or in tandem with approved DPP-IV inhibitors, they could herald a brand new treatment paradigm for type 2 diabetes mellitus. With the passage of the first GPR119 agonist clinical candidates into Phase I trials (Arena/Ortho McNeil APD597; Metabolex MBX-2982; Prosidion/OSI PSN821) and confirmatory reports of clinical proof of concept with respect to glycemic control and incretin release, the spotlight has been set for this new class of therapeutic.

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…GPR119 agonists mediate a unique dual elevation of both insulin and glucagon-FUTURE TYPE 2 DIABETES THERAPY like peptide 1/glucose-dependent insulinotropic peptide levels (Chu et al, 2008;Jones et al, 2009;Kebede et al, 2009;Jones, 2010) making them interesting for a combination with DPP-4 inhibitors (see section III), especially with respect to weight loss. It is not yet established whether the primary determinant of GPR119 efficacy results from its direct insulinotropic or incretin-releasing properties.…”

GPR119 Agonists: A Novel Strategy for Type 2 Diabetes Treatment

“…It is hardly surprising that, based on the strong biological proof of concept generated using the potent, selective agonist molecule 4 [19,30,32]. In recent years, numerous patents describing GPR119 agonists have been disclosed, and several companies have advanced GPR119 agonists into the clinic for the treatment of type 2 diabetes (Table 1, Figure 4 …”

“…Biovitrum has several published patent applications identifying GPR119 agonists which differ in the nature of the central aromatic ring (compounds 13-15) [8,32]. The central heterocyclic ring consisted of a pyridine [37], pyradazine [38], pyrimidine [39], or pyrazine [40] nucleus, which was connected to the piperidine ring via an optionally substituted amino methylene (e.g., Figure 7, 13) or an oxymethylene linker.…”

“…Both of these series of GPR119 modulators, which were reported to exhibit EC50 values ranging from about 50 nM to about 14,000 nM, are described as being useful for treating or preventing obesity, diabetes, metabolic disease, cardiovascular disease or a disorder related to the activity of GPR119 in a patient [32].…”

“…Compounds of this patent application are defined in part by the terminal tetrahydroisoquinoline depicted in 34 ( Figure 12)in February 2007. Compound 35 is representative of IRM's second chemical series of GPR119 modulators which was filed later in 2007 [32,64]. These compounds were reported to be similarly potent in stimulating cAMP in Flp-In-CHO-hGPR119 cells, and are purported to be useful for the treatment or prevention of disorders associated with this receptor.…”