GPR119 agonists currently in development.
Type 2 diabetes (T2DM), also known as non-insulin-dependent diabetes mellitus (NIDDM), manifests with an inability to adequately regulate blood-glucose levels. T2DM may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from T2DM have too little insulin or cannot use insulin effectively. Insulin resistance which refers to the inability of body tissues to respond properly to endogenous insulin develops because of multiple factors, including genetics, obesity, increasing age, and having high blood sugar over long periods of time.
Current therapies for diabetes mellitus include: glucose-lowering effectors, such as metformin which reduces glucose production from the liver; insulin; insulin secretagogues, such as sulphonylureas, which increase insulin production from pancreatic β-cells; activators of the peroxisome proliferator-activated receptor-γ (PPAR-γ), such as the thiazolidinediones, which enhance insulin action; and α-glucosidase inhibitors which interfere with gut glucose production. There are, however, deficiencies associated with currently available treatments, including hypoglycemicepisodes, weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema. Glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors are also widely used in clinical therapy for T2DM. GLP-1 analogs, which require parenteral administration, appear not to be associated with hypoglycemia but cause a relatively high frequency of gastrointestinal side effects. Small molecule DPP-4 inhibitors enhance glucose-dependent insulin release by inhibiting the degradation of endogenous GLP-1. Several nonpeptide, except DPP-4 inhibitors, binding G protein-coupled receptors (GPCRs) have been deorphanized recently and are currently being evaluated as candidate GLP-1 secretagogues for T2DM[5, 6]. Among these, the G protein-coupled receptor 119 (GPR119) has received considerable attention from the pharmaceutical industry in recent years. GPR119 may present an attractive drug target for treating T2DM, and its agonists may therefore represent potential new insulin secretagogues free of the risk of causing hypoglycemia.
GPR119 has been described as a class A (rhodopsin-type) orphan GPCR without close primary sequence relative in the human genome. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion from pancreatic β-cells and increased release of the gut peptides GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY). Preclinical and clinical studies with GPR119 agonists in type 2 diabetes support that GPR119 agonists have been proposed as a novel therapeutic strategy for diabetes. These investigations indicate that orally available, potent, selective, synthetic GPR119 agonists: a) lower blood glucose without hypoglycemia; b) slow diabetes progression; and c) reduce food intake and body weight. This review provides an overview of the recent progress made in the discovery of orally active GPR119 agonists, and outlines the current clinical trial landscape and paints a detailed illustration of the key structural information realized from GPR119 agonist campaigns.
2. GPR119: A historical perspective
2.1. Discovery and characteristics of GPR119
After the discovery of GPR119 in 1999 using data afforded by the Human Genome Project, it was subsequently described in the peer-reviewed literature as a Class A receptor with no close relatives. Independently, this receptor has been studied and described in the literature under various synonyms, including SNORF25 [10, 11], RUP3 , GPCR2 , 19AJ , OSGPR116 , MGC119957, HGPCR2 and glucose-dependent insulinotropic receptor (GDIR) . This potentially confusing nomenclature has now been largely rationalized in favor of the designation “GPR119”.
The human receptor is encoded by a single exon with introns located on the short arm of X- chromosome (Xp26.1) (Figure 1). GPR119 homologs have been identified in several vertebrate species, including the rat, mice, hamster, chimpanzee, rhesus monkey, cattle and dog. Fredriksson et al. (2003) report the rat isoform of GPR119 (accession number AY288429) as being 133 amino acids longer than the mouse and human receptors (468 vs. 335 amino acids). In contrast, Bonini et al. (accession number AR240217) and Ohishi et al. give identical sequences for the rat receptor, which are 335 amino acids in length and have 96% amino-acid identity with mouse GPR119[10, 11, 17].
2.2. GPR119 Receptor Expression
Using methods to detect receptor GPR119 mRNA, it has been proposed that, in human tissues, the pancreas and foetal liver have been consistently identified as major sites of GPR119 mRNA expression, with high expression also being noted in the gastrointestinal tract in several studies, while, in rodents, mRNA was detected in most of the tissues examined [9-11], with the pancreas [12, 18] and gastrointestinal tract, in particular the colon and small intestine, again appearing as major sites of expression. GPR119 expression has also been described in certain regions of the rat brain.
2.3. GPR119 signaling and de-orphanization
High-level expression of GPR119 in transfected HEK293 cells led to an increase in intracellular cAMP levels via activation of adenylate cyclase [10, 11, 19], indicating that this receptor couples efficiently to Gαs. In support of these data, potential endogenous ligands and synthetic small molecule agonists of GPR119 have been shown to increase cAMP levels (Figure 2).
Lysophosphatidylcholine (LPC, Figure 3,
3. GPR119 regulation of insulin and incretin secretion
3.1. GPR119 regulation of insulin secretion
Based on the expression profile and coupling properties of GPR119, it stands to reason that activation of the receptor in pancreatic β cells might lead to enhanced glucose-dependent insulin release. Although the mechanism by which insulin secretion is increase following the activation of GPR119 involves a rise in cAMP, Ning et al. have demonstrated that potentiation of insulin secretion is also dependent on the closure of ATP-sensitive K+ channels and the consequent gating of voltage sensitive calcium channels. The potent, selective GPR119 agonist discovered at Arena Pharmaceuticals, Inc., AR231453 (Figure 3, 4), significantly increased insulin release in HIT-T15 cells (a hamster insulinoma-derived line with robust GPR119 expression) and in rodent islets. By contrast, no effect of this compound could be seen in islets isolated from GPR119-deficient mice, confirming that its effects were indeed mediated by GPR119.
3.2. GPR119 regulation of incretin secretion
GPR119 stimulates the release of GIP, GLP-1 and at least one other L-cell peptide, peptide YY (3-36) (PYY). GPR119 mRNA was found to be expressed at significant levels in intestinal sub-regions that produce GIP and GLP-1. Cellular expression studies have extended these observations by showing that most GLP-1 producing L cells in the ileum and colon also contain GPR119 . This is consistent with data showing high GPR119 expression in most
In considering the actions of GPR119 agonists as pontential mediators of GLP-1 and GIP secretion, and the potential beneficial actions that derive from this, it should not be overlooked that the enteroendocrine cells from which these incretins are released, also secrete a range of additional products, including GLP-2, oxyntomodulin (OXM), cholecystokinin, and PYY from L cells, as well as xenin from K cells. So far, very little attention has been paid to these additional intestinal peptides during analysis of GPR119-mediated responses
4. GPR119 Agonists: Medicinal chemistry
4.1. Clinical trial status and future prospects
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): Ortho-McNeil/Arena (APD-668 and APD-597; both discontinued), Sanofi-Aventis/Metabolex (SAR-260093/MBX-2982; Phase 2), Glaxo-SmithKline (GSK-1292263; Phase 2), Astellas/Prosidion (PSN-821; Phase 2) and Bristol-Meyers Squibb (Phase 1). The following sections provide an overview of the multiple classes of GPR119 agonists, along with the available biological data, reported by various pharmaceutical organizations. Each section is categorized according to applicant.
|GSK-1292263||GlaxoSmithKline||Phase 2||NCT01119846, NCT01218204,|
4.2. Available structures of GPR119 agonists
4.2.1. Arena pharmaceuticals
Arena Pharmaceuticals has been actively pursuing two GPR119 modulators, derived from 4 that were both considered for progression into human clinical, studies as potential drug candidates after the discovery and validation of this receptor as a viable target for the treatment of metabolic disorders. In December 2004, Arena announced a collaboration agreement with Ortho-McNeil Pharmaceutical, Inc., under which two Arena-discovered GPR119 agonists were selected for preclinical development (Arena Pharmaceuticals, Inc., Press Release, December 23, 2004, http://arna.client.shareholder. com/releasedetail.cfm?ReleaseID=320778 ). The first compound, APD668 (also known as JNJ28630355), displayed high GPR119 potency across various species (hEC50 = 0.47 nM, mEC50 = 0.98 nM, rEC50 = 2.51 nM; melanophore dispersion assay) and demonstrated good in vivo activity (3–30 mg/kg, p.o.) in rat and mouse oGTT studies. Compared to a known DPP-IV inhibitor, APD668 (Figure 5,
To tackle the CYP2C9 inhibition we elected to focus primarily on our alternative scaffold, as exemplified by
Compounds effective in stimulating insulin secretion and inhibiting the increase of blood sugar levels have been reported by Astellas. These were derived from a bicyclic scaffold in which a pyrimidine ring was fused to an aromatic (e.g., thiophene, thiazole, and pyridine) or a nonaromatic (e.g., dihydrothiophene, dihydrofuran, and cycloalkyls) heterocycle. Detailed pharmacological data on two disclosed GPR119 agonists from Astellas have been presented. The first generation analog, AS1535907 (Figure 6,
Further SAR optimization resulted in the second generation compound, AS1907417 (hEC50 = 1.1 μM, Figure 6,
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, pyradazine, pyrimidine, or pyrazine nucleus, which was connected to the piperidine ring via an optionally substituted amino methylene (e.g., Figure 7,
4.2.4. Bristol-Myers squibb
The first series of GPR119 agonists reported by Bristol–Myers Squibb featured a [6,5], [6,6], or [6,7] bicyclic central core[41, 42]. Representative examples containing pyrimidine-fused pyrrazole, triazole, and morpholine ring systems are shown in Figure 8. The second BMS series featured a pyridone central core that was N-substituted with the aryl motif and linked to the piperidine motif at the 4-position through an oxygen linker (Figure 8, 19, 20;); pyridazone analogs have also been claimed as GPR119 modulators[43, 44]
Replacement of Arena’s pyrazolopyrimidine ring system with a dihydropyrrolopyrimidine scaffold was shown to be successful by researchers at GlaxoSmithKline[45, 46]. The two initial filings, from July 2006, describe agonists that retain a 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine core unit (Figure 9). The third patent application contains compounds with a benzene, pyridine, pyrazine or pyridazine central core (e.g.,
In addition to the pyrrolopyrimidine scaffold, a series of GPR119 agonists based on monocyclic six-membered aryl and heteroaryl cores have also been reported by GlaxoSmithKline. GSK1292263 (Phase 2, hGPR119 pEC50 = 6.9 nM, rat GPR119 pEC50 = 6.7 nM ) augmented insulin secretion and decreased glucose AUC in rodent glucose tolerance tests; an increased incretin secretion (GLP-1 and GIP) was also observed. The safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of GSK-1292263 were evaluated in a completed randomized, placebo-controlled clinical trial in healthy volunteers (ClinicalTrials.gov Identifier NCT00783549). A total of 69 subjects received single escalating doses of GSK-1292263 (10-400 mg) prior to administration of a 250mg dose given once daily for 2 and 5 days, which was also evaluated in combination with sitagliptin (100 mg). Treatment with GSK-1292263 at all doses was described as well tolerated, with the most common drug-related effects being mild headache, dizziness, hyperhidrosis, flushing and post-oGTT hypoglycemia. Coadministration with sitagliptin increased plasma active GLP-1 concentrations and lowered total GLP-1, GIP and PYY levels; no effects on gastric emptying were observed with GSK1292263. The data support further evaluation of GSK-1292263 for the treatment of T2DM.
Merck has two published patent applications describing GPR119 agonists which retain a 4,4’-bipiperidine scaffold (Figure 10;
In 2006, Schering–Plough filed several patents describing spiro-azetidine and spiro-azetidinone derivatives, which are described as T-calcium channels blockers, GPR119 receptor agonists and Niemann-Pick C1-like protein-1 antagonists, with utility for the treatment of pain, diabetes and disorders of metabolism (Figure 10,
More recent published patent filings from Schering describe selective GPR119 modulators comprised of a fused pyrimidinone core (compounds
GPR119 agonists from Metabolex are based on a five-membered central heterocyclic core that is linked directly to the piperidine motif at its C4 position and to the aryl motif through an oxymethylene spacer[55-58] (Figure 11). Most examples in this application showed agonist activity at 10 μM in the fluorescence resonance energy transfer (FRET) assay corresponding to increased intracellular cAMP levels. Glucose stimulated insulin secretion experiments using isolated rat islets are described and compound
Metabolex advanced their orally available GPR119 agonist MBX-2982 (Figure 4,
Genomics Institute of the Research Foundation (GNF) has disclosed an extensive set of GPR119 agonists containing a heterocyclic sulfonamide as a novel left-side structural motif[61-63]. Compounds of this patent application are defined in part by the terminal tetrahydroisoquinoline depicted in
4.2.9. Prosidion Ltd.
The GPR119 agonist program at Prosidion evolved from their earlier lead PSN632408 (Figure 13, EC50 = 5.6 μM, Emax = 110%). Replacement of the left-side pyridine ring with the more commonly employed methanesulfonyl phenyl motif (Figure 13), while retaining the oxadiazole core, was shown to be tolerated (e.g.,
Applications were filed in 2007 disclosed GPR119 agonists by Prosidion containing a central acyclic alkoxylene or alkylene spacer instead of the oxadiazole core. Compound
More recently, the Prosidion group described GPR119 agonists in which the potentially labile tert-butylcarbamate functionality was replaced with bioisosteric heteroaryl groups, in particular with an oxadiazole similar to Arena’s AR231453. Several azetidine-based GPR119 agonists (Figure 14) have also been disclosed by Prosidion [8, 68, 69]. These analogs featured an appropriately substituted biaryl moiety five-membered heterocycle connected to the azetidine through an oxygen atom (e.g.,
Optimization of the above described chemical series resulted in identification of the clinical candidate PSN821, the structure of which has not been disclosed. In pre-clinical studies, PSN821 has demonstrated pronounced glucose lowering in rodent models of type 2 diabetes with no loss of efficacy on repeated administration, and substantial reductions of body weight in rodent models of obesity. In male diabetic ZDF rats, both acute and chronic oral administration of PSN821, significantly and dose-dependently reduced glucose excursions in an oral glucose tolerance test. In prediabetic male ZDF rats, weeks significantly lowered nonfasting blood glucose concentrations and HbA1c levels compared to vehicle. Furthermore, in weight-stable, dietary-induced obese (DIO) female Wistar rats, daily oral dosing of PSN821 for 4 weeks reduced body weight substantially and significantly by 8.8%, approaching the 10.6% weight loss induced by a high dose of the prescribed anti-obesity agent sibutramine.
In the double-blind, placebo-controlled, ascending single dose first-in-human study, PSN821 was generally well tolerated at doses up to 3000mg in healthy volunteers and 1000mg (the top dose tested) in patients with type 2 diabetes, with no clinically important adverse effects on laboratory tests, 12-lead ECGs or vital signs. Pharmacokinetics showed a profile consistent with once or twice daily dosing. In patients with type 2 diabetes, PSN821 showed substantial and statistically significant reductions in glucose responses to a standard nutrient challenge of approximately 30% at 250mg and 500mg. The data from this study was supportive of progression of PSN821 into a 14-day dosing ascending multiple dose study in healthy subjects and patients with type 2 diabetes and will be submitted for presentation at a scientific meeting together with the data from the multiple ascending dose study.
The discovery team at Prosidion has explored a unique approach of combining DPP-4 inhibition and GPR119 agonism in a single molecule. Introduction of the cyanopyrrolidine pharmacophore of known DPP-4 inhibitors on the aryl motif of their GPR119 agonists provided compounds, which displayed dual activity as agonists of GPR119 and inhibitors of DPP-IV (Figure 14,
4.3. The pharmacophore model for potent GPR119 agonists
Xiaoyun Zhu et al. have generated pharmacophore models using Discovery Studio V2.1 for a diverse set of molecules as GPR119 agonist with an aim to obtain the pharmacophore model that would provide a hypothetical picture of the chemical features responsible for activity. The best hypothesis (Figure 15) consisting of five features, namely, two hydrogen bond acceptors and three hydrophobic features, has a correlation coefficient of 0.969, cost difference of 62.68, RMS of 0.653, and configuration cost of 15.24, suggesting that a highly predictive pharmacophore model was successfully obtained. The Fit-Value and Estimate activity of GSK-1292263, which have completed phase II clinical trials as a GPR119 agonist (Figure 15), based on Hypo1 in Decoy set are 8.8 and 7.7 (nM), respectively. The validated pharmacophore generated can be used to evaluate how well any newly designed compound maps on the pharmacophore before undertaking any further study including synthesis, and also used as a three-dimensional query in database searches to identify compounds with diverse structures that can potentially agonist GPR119.
5. Future directions and concluding remarks
In summary, GPR119 agonists seem to provide a completely novel and previously unexplored approach to incretin therapy in patients with T2DM, increasing glucose-dependent insulin secretion through two complementary mechanisms: directly, through actions on the β cell, and indirectly, through enhancement of GLP-1 and GIP release from the GI tract. It is also worth pointing out the obvious potential advantages that could theoretically be obtained by the co-administration of a GPR119 agonist (with a mechanism as a GLP-1 secretagogue) and a DPP-4 inhibitor (with a mechanism to protect secreted GLP-1), and some preliminary and recent published data support this attractive concept. Such a strategy may not only provide improved glycemic control, but also induce weight loss, a feature observed with GLP-1 mimetics but not with DPP-4 inhibitors. Following the recent entry of the GPR119 agonists MBX-2982, GSK-1292263 and PSN821 into clinical development, the value of these compounds as a new class of therapeutics for type 2 diabetes and associated obesity is likely to be determined within the next few years.
This study was supported by the National Natural Science Foundation of China (No. 81172932) and the Fundamental Research Funds for the Central Universities of China (No. 2J10023 and JKY2011009).
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