G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment

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Perspective

G Protein-Coupled Receptor 119 (GPR119 ) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges Kurt Ritter, Christian Buning, Nis Halland, Christoph Pöverlein, and Lothar Schwink J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.5b01198 • Publication Date (Web): 29 Oct 2015 Downloaded from http://pubs.acs.org on October 31, 2015

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Journal of Medicinal Chemistry

G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges AUTHOR NAMES. Kurt Ritter*, Christian Buning, Nis Halland, Christoph Pöverlein, Lothar Schwink AUTHOR ADDRESS. Sanofi-Aventis Deutschland GmbH, Building G838, Industriepark Hoechst, 65926 Frankfurt, Germany KEYWORDS. GPR119 agonists; Type 2 Diabetes Mellitus; Incretins; GLP-1; Glucosestimulated insulin secretion ABSTRACT. In this perspective recent advances and challenges in the development of GPR119 agonists as new oral anti-diabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on the body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies but many have failed either in phase I or II, and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical

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properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development. Introduction Strict regulation of storage and utilization of nutrients such as glucose and fat in humans is accomplished by a highly effective cross-talk between organs and tissues such as intestine, liver, pancreas, muscle and adipose tissues. The life-sustaining task of food intake and digestion as well as storage and supply of nutrients on demand is maintained by cooperation of cells of different types and location through the controlled secretion and action of specific hormones such as insulin, incretins, e.g. GLP-1 and GIP, and other gut hormones such as PYY. Especially the homeostasis of glucose is of great importance, because glucose is the major source of energy for the brain and an insufficient supply (hypoglycemia) can lead to loss of consciousness. On the other hand, persistently elevated glucose levels (hyperglycemia) are detrimental to the health of blood vessels and many organs and therefore a tight regulation is required. Type 2 diabetes mellitus (T2DM), a progressive chronic disease,1,2 is characterized by the inability of the human body to keep the blood glucose level in the required and balanced range in the fed and/or fasting state. Two major irregularities established in T2DM patients are the altered secretion of insulin from the pancreas (elevated in early stages, reduced or absent in the late stages of the disease) and resistance against the action of insulin in different tissues (muscle, liver, and adipose tissues), which is often exacerbated by concurrent overweight or obesity. Reduced glucose uptake into muscle cells and disproportionate glucose production in the liver lead to a hyperglycemic state. In the long term, chronic hyperglycemia exacerbates the situation by accelerating the decline of the insulin-producing beta-cells in the pancreas, the hallmark in the


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progression of the disease. Commonly, this is accompanied by high blood levels of triglycerides, free fatty acids and other lipids, especially in overweight and obese patients. Chronically elevated blood glucose levels have detrimental effects on blood vessels, nerves, kidney and other organs. Thus, T2DM patients have an increased risk for cardiovascular diseases and often suffer from different stages of retinopathy, neuropathy and nephropathy in various courses of disease.1,2 T2DM therapies mimicking the action of incretin hormones, especially for overweight and obese T2DM patients, have lately been a focus of the pharmaceutical industry due to the lower risk of hypoglycemia and neutral or even beneficial effects on body weight in comparison to sulfonyl urea or insulin treatment.3-5 Injectable GLP-1 analogs with an extended half-life compared to the endogenous hormone (i.e. being resistant to proteolytic cleavage by enzymes such as DPP-IV) demonstrate a strictly glucose-dependent insulin secretion and thus a reduced risk of hypoglycemia. Furthermore, they decrease food intake and promote weight loss, probably due to delayed gastric emptying and induction of satiety. The G protein-coupled receptor 119 (GPR119) has emerged as an important target for a new potential oral treatment of T2DM as evident from the numerous patent applications in this field.6,7 The strong interest stems from animal studies with GPR119 agonists showing a glucosedependent effect on blood glucose levels by concomitant release of insulin from pancreatic betacells and incretins from intestinal cells. The identification and optimization of such agonists has been described in a number of reviews.6-15 However, several clinical candidates (Table 1 and Chart 1) have been discontinued, often without disclosure of the underlying reasons. This perspective will discuss recently published efforts and strategies in overcoming difficulties in the development of GPR119 agonists without claiming to be comprehensive.

Table 1. Overview and status of GPR119 agonists in clinical trials.


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Compound

Ref.

Company

Codevelopment

Highest Development Phase (Indication)

Studies (ClinicalTrial.gov Registry Number)

Status

PSN821 *

6

Astellas (Prosidion)

AstraZeneca did not exercise option

Phase II (T2DM, obesity)

NCT01386099

Discontinued (Nov. 2012)

1 (GSK1292263)

16, 17

GlaxoSmith Kline

Phase II (T2DM, dyslipidemia)

NCT00783459; NCT01101568; NCT01119846; NCT01128621; NCT0218204

2 (MBX-2982)

6, 13

CymaBay Therapeutics (Metabolex)

Phase II (T2DM)

NCT00946972; NCT00871507; NCT00910923

Search for outlicensing

Sanofi returned rights to Metabolex (Apr. 2011)

Discontinued

DS-8500a *

Daiichi Sankyo

Phase II (T2DM)

NCT02222350

Study completed

LEZ763 *

Novartis

PhaseI/II (T2DM)

NCT01619332

Discontinued (Sep. 2014)

3 (APD668)

18, 19

Arena

4 (APD597)

19 21

Arena

ZYG-19 *

Code: JNJ-28630368 Johnson & Johnson terminated collaboration (Dec. 2010) Code: JNJ-38431055 Johnson & Johnson terminated collaboration (Dec. 2010)

Discontinued (Jan. 2008)

Phase I (T2DM)

Phase I (T2DM)

NCT00871507; NCT00910923; NCT00946972; NCT01054118

Discontinued (Aug. 2011)

Zydus Cadila

Phase I (T2DM)

CTRI/2011/12/003013 (Clinical Trials Registry – India)

Search for outlicensing

NCT01240980

Study completed

5 (BMS-903452)

22

BristolMyers Squibb

Phase I (T2DM)

"NN" *

23

Novartis

Phase I

Discontinued (QTc-prolongation)

* (structure not disclosed)

Chart 1. Clinical GPR119 agonists with disclosed structures.


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O N

O S O

N

O

N

O

N 1 (GSK1292263)

N

O

3 (APD668) O

O S

N N H

N

N

O

O O

Cl

N

N

O

O S

4 (APD597)

O N

F

N

2 (MBX-2982)

N

O

N N

F

N

N

O

N

N N N

O O O S

N

S

N

N

N

O Cl 5 (BMS-903452)

Expression, activation and endogenous ligands of GPR119 GPR119 is a class A (rhodopsin-type) G protein-coupled receptor found in different isoforms in several mammalian species ranging from rodents to monkeys and humans.24 GPR119, also named “glucose-dependent insulinotropic receptor”, is comprised of 335 amino acids in its human form. It has little overall sequence homology to other receptors.25 The seven transmembrane receptor GPR119 is expressed predominantly in the beta-cells of the pancreatic islets and in the K- and L-cells of the gastrointestinal tract.26,27 Due to the Gαs-coupling of GPR119 activation increases the intracellular activity of adenylate cyclase and subsequently cyclic AMP levels as shown for example in GPR119-transfected HEK293 cells and HIT-T15 cells with an endogenous expression of GPR119.28,29 GPR119 stimulation in beta-cells augments insulin secretion in a glucose-dependent manner. Enteroendocrine cells release the gut peptides GLP-1, GIP and PYY into the intestinal tissue and the blood stream upon GPR119 activation. Furthermore, elevated plasma levels of GLP-1 and GIP in combination with a GPR119 agonist


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might act in concert on beta-cells via their cognate receptors to elicit an additive or even synergistic effect on insulin release. Lysophospholipids such as oleoyl- and palmitoyl-containing lysophosphatidylcholines have first been proposed as ligands for the (at that time) orphan receptor GPR119, but these findings have been questioned.30 Since the identification of oleoylethanolamide (OEA) the list of putative physiologically relevant ligands of GPR119 has been expanded31 and now includes further N-acylethanolamides such as palmitoyl– and linoleoylethanolamide and other derivatives of oleic acid such as N-oleoyldopamine (OLDA) and 2-oleoylglycerol (2-OG).32-36 However, the discussion about the “true” endogenous ligand(s) in a particular tissue is ongoing due to their often low potency at GPR119 in cellular assays34 and their effects on other receptors involved in metabolism or their role in different signaling processes.36 Furthermore, typically poor solubility limits application of endogenous GPR119 agonists in assays and as a consequence, different synthetic GPR119 agonists have been chosen as reference for the determination of the relative intrinsic activity (IA) for new compounds. Therefore, the use of different reference compounds has to be taken into account when comparing the reported intrinsic activities of GPR119 agonists from various sources.

Key hurdles in lead finding and optimization of GPR119 agonists In order to generate starting points for their optimization programs, most companies entering the GPR119 field have either used high throughput screening and/or derivatization of published agonists, often guided by molecular modelling approaches. The lipophilic nature of the putative endogenous agonists like OEA or 2-OG suggests a strong preference of the orthosteric binding site for hydrophobic ligands. Indeed, this is reflected by the early prototypical agonists reported by Arena, Prosidion and GSK that all combine typical drawbacks of lipophilic compounds, such


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as low aqueous solubility as well as hERG channel and/or CYP enzyme inhibition. Progression of such compounds usually requires advanced formulation techniques and the application of high doses to overcome non-linear PK behavior. Apart from the challenges in designing GPR119 agonists with acceptable physicochemical properties, the optimization of the pharmacodynamic parameters such as potency at the receptor and extent of activation (maximal intrinsic activity) has proven to be far from trivial. Medicinal chemistry teams have succeeded in preparing highly potent GPR119 agonists with activities in the low nanomolar range, whereas increasing the maximal receptor activation has been more difficult. Which extent of receptor activation (partial, full or even superagonism) is required to achieve an optimal beneficial therapeutic effect is still an unresolved question. Since rodent GPR119 receptor sequences differ from the human receptor, the development of GPR119 agonists might have been complicated by poor translation of murine or rat in vivo models to human clinical trials. Furthermore, tachyphylaxis, a wellknown phenomenon in activation of GPCRs, needs to be considered as a possible limitation for a chronic treatment. Finally, a thorough understanding of the relative contributions of receptor activation at the two major sites of GPR119 expression, i.e. gut and pancreas, to the overall pharmacological effect might help to guide the design of agonists. Taken all together, this leads to the important question whether improved 2nd generation GPR119 agonists will be able to provide diabetic patients with additional benefits, besides glucose lowering, that initially attracted the intense interest. In the following discussion recent progress made by the various drug discovery teams in addressing the challenges mentioned above will be described in detail. Based on the seminal work by Arena and Prosidion on GPR119 agonists and subsequent efforts of many pharmaceutical companies, a well-defined structural architecture has emerged


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that displays high agonistic activity. Most reported GPR119 agonists contain (a) a (hetero)aryl moiety (“head group”) acting as, or being substituted with a hydrogen bond acceptor, and (b) a piperidine (or piperazine) ring N-substituted with a moiety containing a hydrogen bond accepting group in a lipophilic environment (“tail group”), such as carbamates, 5-substituted pyrimidines or substituted oxadiazoles (Figure 1). The spacer between the two pharmacophores ensures the right distance and optimal orientation relative to each other for interaction with the receptor.37

(Het)-Aryl

Spacer

X

H-Bond Acceptor

N

X = CH, N "Head group" O O S A A = CH, N

"Tail group" R1 N O N N

N

R2 N

N N N N

O O R3

Figure 1. Typical molecular architecture of synthetic GPR119 agonists.

Arena-like GPR119 agonists with pyrimidine-containing spacer Arena. Arena’s prototypical GPR119 agonist 6 (AR231453) is selective and active across species and significantly lowered blood glucose levels after oral administration of 20 mg/kg in mice.38 Rescaffolding to a 6,5-fused heterobicyclic ring system lacking the unwanted aniline and nitro functions and reversing the orientation of the piperidine ring led to 3 with a hEC50 of 23 nM (Scheme 1) that was selected as a clinical candidate based on its favorable overall preclinical profile.18 The compound showed in vivo activity in acute oral glucose tolerance tests (oGTT) after administration to rodents and cynomolgus monkeys. Chronic treatment of male Zucker Diabetic Fatty (ZDF) rats with 30 mg/kg 3 over eight weeks resulted in significantly lower levels


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of blood glucose and HbA1c (HbA1c = 4.7% vs 7.4% for vehicle) and thus prevented the development of diabetes in treated animals. Drawbacks of 3 were its strong inhibition of the CYP2C9 isoform (IC50 = 0.1 µM) and its moderate inhibition of the hERG channel in a patch clamp assay (IC50 = 3 µM).18 In clinical studies accumulation of a hydroxylated, inactive metabolite 7 was found. After 14 days of dosing the plasma ratio of 7 to the parent compound 3 was increased to 4.3 to 5.1 fold. The high concentration and the observed long half-life (41-50 h) of the metabolite 7 raised concerns for the further development of 3. In order to identify a second generation candidate with an improved overall profile, Arena returned to the monocyclic pyrimidine-containing spacer.19,39

Scheme 1. Arena’s GPR119 agonists with pyrimidine-containing spacer. O

O S

N

F

N H

1st round optimization

N N NO2

O O O S

N

N F

N

N

O R

O

N N

O N 6 (AR231453), hEC50 = 5.9 nM

3 (R = H), hEC50 = 23 nM 7 (R = OH) inactive metabolite

2nd round optimization

O

O

O S

N N

N H

N

N

O O

N

O X

O

O S

N

N

N

O

O

O F

4 (X = OMe), hEC50 = 46 nM

9, hEC50 = 13.8 nM

8 (X = F), hEC50 = 132 nM

A second round of optimization led to 4, a potent agonist at human and rat GPR119 (hEC50 = 46 nM, 75% IA; rEC50 = 421 nM, 85% IA). The highly permeable compound 4 demonstrated slightly increased solubility (0.31 mg/mL at pH = 2.0 and 0.11 mg/mL at pH = 7.0) together with reduced inhibition of CYP2C9 (IC50 ~8 µM) and the hERG channel (IC50 = 13 µM).


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Significantly reduced oxidation of the terminal isopropyl group adds to a favorable overall metabolic profile avoiding the accumulation of metabolites observed for 3. The positive outcome of an in vivo evaluation of 4 in established diabetic animal models and its overall good ADME and safety profile led to its progression into clinical trials.19 In a study in healthy male adults with a dose-escalating regimen (2.5-800 mg), oral administration of 4 was well tolerated and not associated with any hypoglycemic events. The pharmacokinetics of the compound (exposure, half-life) was consistent with once daily dosing.20 In the following single (100 or 500 mg orally) and multiple-dose studies (500 mg qd over 14 days) in T2DM patients, 4 demonstrated slight increases in gut hormones over placebo. However, the overall increase in insulin secretion and glucose-lowering effects were not statistically significant preventing further development of 4.21 Arena recently reported further modifications within this series.39 Whereas the fluoropyrimidine 8 retained only moderate GPR119 activity (hEC50 = 132 nM) without improvement with regard to CYP2C9 inhibition over 4, the bis-ether derivative 9 showed similar potency to 4 with reduced inhibition of CYP2C9 (IC50 = 25.7 µM). Synergistic effects (70% suppression of glucose excursion) of a combination of the GPR119 agonist 9 (3 mg/kg) and the approved DPPIV inhibitor sitagliptin (3 mg/kg) in a rat oral glucose tolerance test were observed.39 Several GPR119 agonists reported by other companies can be derived from an APD597-like starting point by formal cyclization from the central pyrimidine moiety to a linking nitrogen atom (Scheme 2, path a or b) or from the linking nitrogen atom towards the aryl sulfone moiety (Scheme 2, path c). This use of scaffolds with larger aromatic π-systems and/or reduced flexibility is often accompanied by further reduction of the already limited solubility.

Scheme 2. GPR119 agonists derived from 4 following different formal cyclization paths.


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GlaxoSmithKline

Arena O

O O S

N

N

N

O O

a

N

N

N

O

N H c

c

N

N

O O

O S

N

b

b

12 (X = NH), hEC50 = 5740 nM

Takeda

Bristol-Myers Squibb

O X

N N

Y

N O

O N O

O O S

N N

N

N

N

O

O

O S

N

O Cl

14 (X = N, Y = CH), hEC50 = 17 nM

O

11 (X = O), hEC50 = 150 nM

b

4, hEC50 = 46 nM

O O S

N

N N

O a

O

N

X

O

F 10 (GSK1104252A), hEC50 = 50 nM

Roche O

O S

16, hEC50 = 7.7 nM

N H

N

N

O

N O 13

15 (X = CH, Y = N), hEC50 = 8800 nM

GSK. After extensive optimization, GSK identified the dihydro-pyrrolopyrimidine 10 (GSK1104252A), also a close analog of 3, as the best compromise with regard to potency and plasma exposure.40 In an oGTT in normal rats oral administration of 10 (10 mg/kg) decreased the glucose excursion by 38%, comparable to the effect of 10 mg/kg sitagliptin used as positive control. Furthermore, the compound reduced gastric emptying significantly in fasted Sprague Dawley rats as compared to the vehicle. Several companies have prepared analogs of 4 in which the central heteroaromatic ring has been modified by formal cyclization along path b (Scheme 2).41-43 Roche. Interestingly, in a matched pair (11, X = O vs 12, X = NH) within Roche’s pyrazolopyrimidine series, the oxygen-linked agonist is nearly 40-fold more active than the Nlinked derivative (Scheme 2). However, besides poor solubility, a strong inhibition of the hERG channel was observed. The 4-methylsulfonylphenoxy group in 11 was a further liability, as it was found to be replaced by glutathione in a metabolite study in mouse hepatocytes.41 BMS. Compound 13 with a pyrimido-oxazine core is another example of GPR119 agonists with a cyclization following path b (Scheme 2) that has been reported in patent applications by BMS and others.42-44


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Takeda. At Takeda, merging of proprietary hit structures with structures reported by Arena led to a series with a 5-(methylsulfonyl)indoline motif (14 - 16, Scheme 2).45 The huge difference in activity of the matched pair 14 (hEC50 = 17 nM) vs 15 (hEC50 = 8800 nM) can be explained by the strong preference for an anti-conformation of the lone pairs of the pyrimidine nitrogen and the adjacent oxygen. This likely gives rise to dissimilar preferred conformations of the piperidine-4-yl-oxypyrimidine moiety and 14 probably favors the pharmacologically more relevant conformation for binding and activation of the receptor. The slightly more active oxadiazole derivative 16 (hEC50 = 7.7 nM) showed the expected lowering of plasma glucose excursion and increase in glucose-dependent insulin excretion in a rat oGTT (10 mg/kg po). Pfizer as well as Merck elaborated conformationally restricted bridged piperidine analogs by starting from Arena’s partial GPR119 agonist 17 (hEC50 = 14 nM, 21% IA).46-48

Scheme 3. GPR119 agonists featuring conformationally restricted bridged piperidines. Arena N N

Pfizer

O N

O

Agonist

N

N

O N

O

Antagonist

N

O

N O

O

18, hEC50 = 65 nM

O

N O

O

N 17, hEC50 = 14 nM

N

N O

O O

19, hEC50 > 10 µM

O

Merck N N

N

O

N O

N

N

O

exo

N

O O

N

N

O

O 22, hEC50 = 24 nM NC

N

Cl

20, hEC50 = 636 nM N N N N

N

N H

N

O O

N

O

F

N

23, hEC50 = 3 nM

N

O

S

N

O

O 21, hEC50 = 22 nM


12

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Pfizer. Pfizer disclosed oxabicyclic derivatives such as 18 and 19 (Scheme 3) to freeze axial and equatorial conformations of the oxy-substituent at the piperidine ring of 17. Compound 18 (hEC50 = 65 nM, 78% IA) had agonistic properties with increased intrinsic activity compared to 17, whereas the isomer 19 surprisingly showed antagonistic activity (Kb = 25 nM), a rare example of an agonist-antagonist switch within a pair of isomers.46 In an extension to this work Pfizer embedded the piperidine moiety in a tricyclic cage as exemplified by compound 20 (hEC50 = 636 nM, 81% IA).47 The Pfizer team was successful in increasing potency by replacing the methyl-pyridine moiety by a tetrazolyl-substituted phenyl ring (21, hEC50 = 22 nM, 101% IA). Low solubility of 21 (i.e. 0.7 µg/mL at pH 7.4) triggered the use of an amorphous spray dried dispersion of 21 with hydroxypropylmethylcellulose acetate succinate for in vivo studies. However, in pharmacokinetic studies in beagle dogs bioavailability decreased from 87% to 32% when increasing the dose from 10 to 100 mg/kg. Due to concerns that solubility-limited absorption would prevent the establishment of a sufficient margin above the projected efficacious exposure in human, the series was terminated. Merck. Merck also reported GPR119 agonists in which the piperidine ring has been rigidified by a carbon-bridge as exemplified by the nortropanol derivatives 22 and 23.48 The exo-derivative 22, having a similar hGPR119 activity compared to 17, was only a partial agonist at the mouse receptor leading to poor glucose lowering in the oGTT assay in mice. This challenge was solved by changing the carbamate to a sulfonamide. Using a cyclopropylsulfonamide and replacing the O-linked methylpyridinol with a substituted N-linked aniline led to the highly potent full agonist 23 (hEC50 = 3 nM, IA = 96%; mEC50 = 140 nM, IA = 110%). In an oGTT in lean mice, 23 showed a lowering of blood glucose excursion of 30% and 39% at 10 mg/kg and 30 mg/kg po, respectively.


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Related conformationally restricted GPR119 agonists containing the classic Arena 5nitropyrimidine spacer were reported by researchers at Kangwon National University to have similar agonist activity and efficacy.49,50 In summary, several companies and academic groups have prepared GPR119 agonists based on the original Arena compounds and introduced additional ring systems in a creative manner. This led to a number of novel structures exploiting this popular pharmacophore. However, the introduction of additional conformational rigidity did not lead to pharmacologically superior agonists and did not effectively address low solubility and the translational issues related to species differences between human and rodent GPR119 activity and efficacy.

Prosidion-like GPR119 agonists In their article detailing the identification of OEA as endogenous GPR119 ligand, Prosidion reported their lead compound 24 (PSN632408, EC50 = 1900 nM) displaying similar agonistic activity as OEA (EC50 = 2900 nM) in a cAMP assay (Figure 2).31 Increase in potency and intrinsic activity in comparison to OEA was achieved by replacement of the pyridine ring by the methylsulfonylphenyl moiety and modification of the spacer, as exemplified by compounds 25 (PSN-119-2) and 26 (PSN-119-1M).15 Many companies have reported series which correspond to Prosidion-like GPR119 agonists taking advantage of an easily assembled ether unit to vary both spacer type and length and thus the orientation between the terminal groups.6-15


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Spacer Alkoxy/Hetaryloxy

(Het)-Aryl

H-Bond Acceptor

N

X

X = CH, N O

Prosidion N O

N O

O

N

O

O

N

N

O

N

F

N

O

F

N O

O

O

S

O

O 25 (PSN119-2), EC50 = 400 nM (reporter assay in yeast expressing hGPR119)

24 (PSN632408), hEC50 = 1900 nM

O

O

S 26 (PSN119-1M), EC50 = 200 nM (reporter assay in yeast expressing hGPR119)

Astra Zeneca N O O S

O

O N

CN

N O

N

O

N

O O S

O

N

N N

N

O N

N

O CF3

O N

O 32, hEC50 = 11 nM

N

N N

33, hEC50 = 9 nM

N

CN

O

N N

O

CF3

N N

N

31, hEC50 = 4 nM

N

N O

N O

O N

N

N

O

F

S

CN

N

N

N

CF3

N

O

CF3 30, hEC50 = 20 nM

N N

29, hEC50 = 6 nM

F O

N O

N

O N

N

N

CN

N

28, hEC50 = 5 nM

N O

O N

N

27, hEC50 = 65 nM CN

N O

N

N O

34, hEC50 = 11 nM

Bristol-Myers Squibb O

O S

O O

O S

O O N

N

N

O S

N

N

N

F

36, hEC50 = 133 nM

N

O O

O

O

O

O

O

O S

O

N

N F

O

37, hEC50 = 18 nM

Cl

N N

N

O Cl 5, hEC50 = 14 nM

O 35, hEC50 = 1700 nM Sanwa Kagaku Kenkyusho

O

O

O S

O

N

O O

N H

N H

N

N N

38, hEC50 = 2610 nM

39, hEC50 = 51 nM

O N O

N H

N

N

O

N H

F

N 40, hEC50 = 14 nM

N

N O N

41, hEC50 = 33 nM

Figure 2. Prosidion-like GPR119 agonists.


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As a result of these efforts PSN821 (structure not disclosed) from Prosidion (now Astellas), 2 from Metabolex (now CymaBay Therapeutics) and 1 from GSK have entered the clinical stage (Table 1) and their preclinical data and results from the first clinical trials have been reported in some detail.11,15 PSN821 and 1 have been discontinued after phase II trials, while CymaBay is exploring partnering options for 2 at the phase II stage. GSK. GSK has published their results for the treatment of T2DM patients with 1, but in none of the studies clinically meaningful effects on glucose or insulin levels were observed after two weeks of treatment at doses up to 600 mg qd or 300 mg bid.16,17 No weight loss was seen, possibly due to the short treatment period, but levels of the gut hormone PYY were elevated. Surprisingly, 1 was found to increase HDL-cholesterol while also markedly decreasing LDLcholesterol and triglyceride levels as compared to placebo. AstraZeneca. The work of AstraZeneca is an illustrative example of the difficulties related to the multiparameter optimization of GPR119 agonists.51-54 Their initial lead compound 27 suffered from poor aqueous solubility (0.03 µM) despite a moderate lipophilicity (logD = 3.2). Analysis of the crystal packing of 27 revealed interactions between the pyrimidine moieties of adjacent molecules as well as a set of polar interactions of the terminal sulfone groups orientated towards each other. Introduction of a methyl group into the piperidine moiety disfavored the pyrimidine interaction. Further investigations revealed the 3-cyano pyridine group as a bioisostere for the methylsulfonyl-phenyl group. Incorporation of both solubility-mediating groups resulted in 28 with good potency and intrinsic activity at human and rodent GPR119 combined with improved solubility (24 µM). Replacement of the acid-labile Boc group by oxadiazoles and subsequent optimization led to the compound 29, a potent GPR119 agonist with a slightly reduced solubility (6 µM), but good cellular permeability and a satisfactory selectivity


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profile. 29 showed glucose lowering activity only in wild-type mice, but not in GPR119 knockout mice.51 This demonstrated unambiguously that the biological effects are exclusively due to GPR119 agonism ruling out additional off-target activities as seen with previous GPR119 agonists from AstraZeneca.52

High-dose PK studies with crystalline material proved that

sufficient exposure could be achieved in rodents and dogs enabling meaningful preclinical toxicity testing. However, 29 caused tonic-clonic convulsions in a third of the treated animals in mouse toxicity studies (day 10, dose 300 mg/kg) raising doubts about a sufficient safety margin. Testing of several compounds in an in vitro hippocampal brain slice assay indicated a link between the 3-cyano pyridine moiety and the observed CNS effects. The AstraZeneca team then turned their attention back to the original sulfones such as 31, which brought back known issues such as low solubility and hERG inhibition (IC50 = 3.6 µM).53 The corresponding benzyl sulfone 32 had reduced hERG activity and was tested negative in the hippocampal brain slice assay. Despite poor solubility (1.8 µM at pH 7.4) 32 displayed a good pharmacokinetic profile and exhibited in vivo efficacy in murine models at doses between 5 and 15 mg/kg. During the course of the optimization of this series a 3-trifluoromethyl-oxetan-3-yl-oxycarbonyl moiety was introduced as a Boc-replacement. Compound 30, containing this new carbamate motif, was reported to combine a relatively high solubility (110 µM at pH 7.4) with increased metabolic stability and displayed a good hGPR119 activity (hEC50 = 20 nM).54 Clear interspecies differences were found in the in vitro pharmacology of conformationally restricted piperazine derivatives such as 33 and 34. While full agonism was observed in the human GPR119 assay, only partial agonism was observed in the murine system.55 BMS. At BMS the use of a pharmacophore model derived from competitor compounds, such as Prosidion’s 24 and Arena’s 3, led to the design of pyridone 35 (hEC50 = 1700 nM, 70% IA).22


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Removal of a methylene group from the spacer provided compound 36 with a 10-fold increase in potency (hEC50 = 133 nM, 80% IA). Further replacement of the carbamate moiety by a substituted pyrimidine and introduction of a fluorine atom provided the potent agonist 37. In a 21-day study in 6-week old db/db mice, 37 (30 mg/kg qd) caused a significant reduction in the HbA1c level comparable to metformin, but due to the short half-life once daily dosing at doses below 30 mg/kg was not possible. Replacement of the metabolically labile 5-propyl-pyrimidine with the 5-chloro-pyrimidine group and introduction of another chlorine atom to the pyridone moiety resulted in the clinical candidate 5 with increased metabolic stability.22 The agonist 5 with a hEC50 of 14 nM exhibited a long half-life of 15 hours in mice and 22 hours in rats. As for most GPR119 agonists, 5 suffered from poor aqueous solubility which caused concerns about solubility limited absorption. Use of an amorphous spray dried dispersion of 5 in hydroxypropyl cellulose resulted in an oral bioavailability in rats of 87% as compared to 33% achieved with a crystalline suspension at a 5 mg/kg dose. Furthermore, 5 showed an excellent in vitro profile with regard to CYP inhibition, PXR activation, cytotoxicity and none or only minimal activity in a test panel of 95 different GPCRs and enzymes with the exception of the hERG channel (IC50 = 1.4 µM). However, electrophysiology studies in rabbits and cynomolgus monkeys did not show any significant effects at plasma concentrations up to 20 µM. The acute in vivo efficacy of 5 was demonstrated in an oGTT in male C57/Bl6 mice. Tested doses of 0.1, 0.3 and 1 mg/kg showed a reduction of glucose excursion of 37 - 40% as compared to the vehicle control. In a cannulated Sprague-Dawley rat model treatment with 0.3 mg/kg 5 given one hour before an oral glucose challenge increased active GLP-1 levels over vehicle at all time points. Synergistic effects on GLP-1 levels were observed in combination with a BMS DPP-IV inhibitor. In a three week study in 6-week old db/db mice a significant reduction of


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fasting plasma glucose and an increase of fasting plasma insulin on day 21 were seen with doses as low as 0.03 mg/kg/d. A phase I dose escalation study proved the safety and tolerability of 5 with single dosing in the range from 0.1 to 120 mg in normal healthy volunteers and showed a dose proportional increase in exposure. A statistically non-significant trend towards increase of the total GLP-1 plasma level was observed during the first 24 hours of treatment.22 Sanwa Kagaku Kenkyusho. The N-linked GPR119 agonists developed by the laboratories of Sanwa Kagaku Kenkyusho show similarity to Prosidion’s O-linked agonists such as 26. Starting from the screening hit 38 (hEC50 = 2610 nM, 56% IA), modification of the amide to a shorter amine spacer in combination with an aminoindanone head group resulted in 39 (hEC50 = 51 nM, 113% IA).56 It showed a dose-dependent lowering of the blood glucose excursion in an oGTT in mice by 29% and 38% at 3 and 10 mg/kg, respectively. Modification of the head group and adding a methyl group to the linker gave racemic 40 (hEC50 = 14 nM, 112% IA) causing a delay of gastric emptying and an increase in total plasma GLP-1 level in mice.57 The best compound (41, hEC50 = 33 nM, 100% IA) with a fluorine substituent in the alkyl spacer displayed good oral bioavailability in rats (58%) and mice (68%), low clearance in rats (0.89 L/h/kg), and an acceptable solubility of 40.7 µM at pH 6.5. First safety tests showed no serious adverse effects.58

Different Strategies for Spacer Rigidization Several groups have attempted to introduce conformational constraints into the spacer region of GPR119 agonists (Scheme 4).

Scheme 4. Different strategies for spacer rigidization.


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Boehringer Ingelheim

F

N O

F

NC

O

N O

H N

N O

H N

F

O

N

42, hEC50 = 93 nM

F

F

S O

43, hEC50 = 30 nM

Bristol-Myers Squibb

N O

H N

O

F

NC

O N

N

O N

N

N O

44, hEC50 = 21 nM

Kowa

R1 R

N R2

O S N O

O N

X

O

45, inactive compounds

CF3 O

S O

N

O

O

O

N N

N

X 46 (R = H, X = H), hEC50 = 82 nM 49, hEC50 = 54 nM

47 (R = H, X = F), hEC50 = 2 nM 48 (R = OH, X = F), hEC50 = 16 nM Merck NC

O N

N

N

N

O

N

N N

50, hEC50 = 3600 nM

51, hEC50 = 19 nM N

N

N

NC

Cl N

O O S

O

N

O

N

52, hEC50 = 2 nM

53, hEC50 = 4 nM

54, hEC50 = 2.1 nM

Pfizer

Arena

O

N N

N

O S O

F

O O

Rigidization

HN

O

O

N

O O S

O

O

N N

N

Switch

N

58, hEC50 = 260 nM

CF3 O

O O S

O N

N N

O

N

O O S

N N

59, hEC50 = 863 nM

N N

O

F 56, hEC50 = 3 nM

N

F

57, hEC50 = 47 nM O

O

N N

O

N

N 55, hEC50 = 5.9 nM

O S O

O

N

F O O S

O

N

O S O

N

N N

N

different spacer

N

N

N N

F 60, hEC50 = 83 nM

Boehringer Ingelheim. Scientists at Boehringer generated virtual libraries with different spiropiperidine scaffolds and prioritized them according to their alignment to known GPR119 agonists.59 Subsequent synthesis of the “virtual hits” in a combinatorial library format of 40-90 compounds for each scaffold resulted in a new lead series containing a 1-oxa-2,8-diazaspiro[4.5]-dec-2-enyl-moiety, exemplified by the full agonist 42 (hEC50 = 93 nM, 170% IA).


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Further improvement in activity was achieved by replacing the Boc-group with a 3-phenyl-1,2,4oxadiazole (43, hEC50 = 30 nM) and the cyano group with a methylsulfinyl group (44, hEC50 = 21 nM). BMS.

The initial

design

of GPR119

agonists

with

a phenyl-substituted

spiro-

dihydrobenzofuran of the general structure 45 at BMS was unsuccessful. However, replacement of the phenyl group with a tetrahydropyridine ring and turning the point of spiro-fusion into a bond led to the potent GPR119 agonist 46.60 Incorporation of two fluorine atoms (47) provided a strong enhancement in in vitro activity, but poor aqueous solubility was noted as a major issue of the series (generally 99% for cynomolgus monkey). Pfizer. Pfizer published novel, but metabolically labile GPR119 agonists such as 70 (hEC50 = 13 nM, 87% IA) with an unique 2-(2,3,6-trifluorophenyl)acetamide group.79 Reducing the number of fluorine atoms or replacing them with typical GPR119 pharmacophoric groups such as methylsulfone or tetrazole led to potency decrease in agonist activity without improvement of metabolic stability. On the other hand, introduction of a fluorine atom to the alkyl chain ((S)-71, hEC50 = 80 nM, 107% IA) reduced lipophilicity and metabolic oxidation as indicated by decreased intrinsic clearance (CLint = 42 mL/min/kg (71) vs CLint > 300 mL/min/kg (70) in human liver microsomes). NMR-studies indicated a conformational restriction of 71 by the known gauche effect in N-β-fluoroethylamides. The authors claim that this is responsible for the large split in potency between S-enantiomer 71 and R-enantiomer 72 (hEC50 = 1380 nM, 100% IA).79 However, the series had to be abandoned due to the formation of reactive metabolites by a CYP3A4-mediated oxidation of the key trifluorophenyl moiety. Genomics Institute of the Novartis Research Foundation. In the search for new structural motifs for GPR119 agonists, 73 was identified in a high throughput screening campaign.80 The metabolically labile and poorly soluble compound displayed moderate potency at the human receptor (hEC50 = 200 nM). Introduction of a methyl group at the benzylic carbon and changes of substituents at the aryl rings led to the chiral compound 74 with enhanced potency (hEC50 = 10 nM, 80% IA) which displayed only marginal activity in a rat oGTT study.81 An increase in potency was achieved by cyclization of the benzylic residue to the heterocyclic core as exemplified in 75 (hEC50 = 0.5 nM, 85% IA), however this was accompanied by a further decrease in solubility and by an increase in in vitro hepatic clearance. Introduction of polar


26

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groups led to the full agonist 76 (hEC50 = 15 nM, 100% IA) with increased solubility (58 µM at pH 6.8) which demonstrated a 37% glucose-AUC reduction in a rat oGTT at a 30 mg/kg qd dose after two weeks.81

Summary and Outlook Despite enormous efforts by many pharmaceutical companies, none of the GPR119 agonists developed so far has fulfilled the original hope for a new oral treatment for type 2 diabetes with reduced hypoglycemic risk and an additional beneficial effect on body weight. It is uncertain at the moment if this is due to a basic lack of translatability of the pharmacodynamic effects seen in preclinical disease models, or if it is just a reflection of suboptimal physicochemical and/or physiological properties of currently available GPR119 agonists. A sufficient exposure of a compound with potent GPR119 agonism and high intrinsic activity might be needed for an adequate release of insulin and incretins to provide a sustained glucose lowering effect in T2DM patients. High potency of synthetic GPR119 ligands is often accompanied by a high lipophilicity in the molecule. Extensive optimization led to many examples including clinical candidates with sufficient metabolic stability; however the poor physicochemical properties of these agonists preclude the necessary exposure being easily reached. It might be speculated that the typically highly permeable compounds suffer from solubility/dissolution-limited absorption. Thus, special formulations and solubilizing technologies such as cocrystallization, nanosuspension or spray dried dispersion have been used frequently, but often without success. Furthermore, the safety requirements for the treatment of a chronic disease such as T2DM, especially in elderly patient cohorts with several comorbidities, are quite demanding. The typically high lipophilicity and aromatic character of GPR119 agonists bring along issues such as


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CYP and hERG inhibition as well as CNS side effects enforcing additional rounds of optimization or requiring safety studies before or during development, which contributed to the high rates of attrition. A potential way around most safety concerns would be the design of nonsystemic agonists addressing only intestinal GPR119, although this might also restrict the desired pharmacodynamic effects as the direct impact on the pancreatic beta-cells would be lost. Despite the many constraints and challenges described above, it might still be possible to design new GPR119 agonists of a 2nd or 3rd generation with the right balance of physiological and physicochemical properties. Further interest might arise from confirmation of findings of a positive influence on beta-cell function and mass by GPR119 agonist treatment in animal studies. Additive or synergistic effects of a combination with DPP-IV inhibitors have to be examined in long term studies (in humans). The question if a satisfying therapeutic effect can be achieved will only be answered by clinical trials with GPR119 agonists of optimal efficacy and suitable pharmacokinetics driven by adequate physicochemical properties.


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AUTHOR INFORMATION Corresponding Author *Phone: +49 69 305 29027. Fax: +49 69 305 942805. E-mail: [email protected]. Author Contributions The manuscript was written through contributions of all authors. Notes The authors declare no competing financial interest. Biographies All authors are currently employees of Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Christian Buning received his Ph.D. in bioinorganic chemistry from the Ruprecht-KarlsUniversity Heidelberg, Germany, in 1998 under the supervision of Prof. P. Comba. After a postdoctoral stay with Prof. T. Lengauer (German National Research Center for Information Technology, St. Augustin (now Fraunhofer Gesellschaft), Germany, working on structure-based methods and virtual screening, he joined Aventis, now Sanofi, in 2002 as computational chemist with a focus on metabolic and cardiovascular diseases. Nis Halland obtained his Ph.D. in organic chemistry in 2003 from Aarhus University, Denmark, under the supervision of Professor K. A. Jørgensen and was granted a two year Marie-Curie fellowship to do research in an industrial setting at Aventis, now Sanofi. In 2006 he joined Sanofi as a medicinal chemist.


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Christoph Pöverlein received his Ph.D. in organic chemistry from the Ludwig-MaximiliansUniversity München, Germany, in 2008 under the supervision of Prof. T. Lindel. After a postdoctoral stay with Prof. A. G. M. Barrett (Imperial College, London) working on the total synthesis of natural products, he joined Sanofi end of 2009 as a medicinal chemist. Kurt Ritter obtained his Ph.D. in organic chemistry in 1985 from the Eberhard-Karls-University Tübingen, Germany, under the supervision of Prof. M. Hanack. After completion of a postdoctoral appointment at Harvard University, Cambridge, USA, with Prof. E. J. Corey, he spent two years at the University of Heidelberg, Germany. From 1989 to 1995 he worked as a medicinal chemist at BASF AG in Ludwigshafen (Germany), then moved back to the US to establish a medicinal chemistry group at the BASF Bioresearch Corporation in Worcester (since 2000 Abbott Bioresearch Center). In 2001, he joined Aventis, now Sanofi, and worked on a number of different projects in the area of cardiovascular and metabolic diseases. Lothar Schwink received his Ph.D. in organic chemistry from the Philipps-University Marburg, Germany, in 1997 under the supervision of Prof. P. Knochel. After a postdoctoral stay with Prof. L. E. Overman (University of California, Irvine, USA) working on natural product synthesis, he joined Hoechst Marion Roussel, now Sanofi, in 1999, as a medicinal chemist with a focus on GPCR modulators for metabolic diseases.

ACKNOWLEDGMENTS We thank Heiner Glombik and John Weston for valuable suggestions and comments.

ABBREVIATIONS USED


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ADME, absorption, distribution, metabolism, excretion; AMP, adenosine monophosphate; AUC, area under the curve; Boc, tert-butyloxycarbonyl; bid, (bis in die) twice daily, BMS, BristolMyers Squibb; CLint, intrinsic clearance; CNS, central nervous system; CV, cardiovascular; CYP, cytochrome P450; DPP-IV, dipeptidyl peptidase IV ; h, human; hERG, human Ether-a-gogo Related Gene; F, bioavailability; FaSSIF, fasted state simulated intestinal fluid; GLP-1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide; GPR G-protein coupled receptor; GSK, GlaxoSmithKline; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; HLM, human liver microsomes; HTS, high throughput screening; IA, intrinsic activity; LDL, lowdensity lipoprotein; m, murine; OEA, oleoylethanolamide; oGTT, oral glucose tolerance test; OLDA, N-oleoyldopamine; 2-OG, 2-oleoylglycerol; qd, (quaque die) once daily; PEG, polyethylene glycol; po (per os) oral; PXR, pregnane X receptor; PYY, (pancreatic) peptide YY; T2DM, Type 2 Diabetes Mellitus; ZDF, Zucker Diabetic Fatty.

REFERENCES (1)

World

Health

Organization

(WHO)

Diabetes

Fact

Sheets

No.312,

2013.

http://www.who.int/mediacentre/factsheets/fs312/en/ (2) Center for Disease Control and Prevention (CD) National Diabetes Statistics Report 2014. http://www.cdc.gov/diabetes/pubs/statsreport14.htm (3) Lorenz, M.; Evers, A.; Wagner, M. Recent progress and future options in the development of GLP-1 receptor agonists for the treatment of diabesity. Bioorg. Med. Chem. Lett. 2013, 23, 4011-4018.


31


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 46

(4) Albrechtsen, N. J. W.; Kuhre, R. E.; Deacon, C. F.; Holst, J. J. Targeting the intestinal Lcell for obesity and type 2 diabetes treatment. Expert Rev. Endocrinol. Metab. 2013, 9, 61-72. (5) Manandhar, B.; Ahn, J.-M. Glucagon-like peptide-1 (GLP-1) analogs: Recent advances, new possibilities, and therapeutic implications. J. Med. Chem. 2015, 58, 1020–1037. (6) Jones, R. M.; Leonard, J. N.; Buzard, D. J.; Lehmann, J. GPR119 agonists for the treatment of type 2 diabetes. J. Expert Opin. Ther. Pat. 2009, 19, 1339-1359. (7) Buzard, D. J.; Lehmann, J.; Han, S.; Jones, R. M. GPR119 agonists 2009-2011. Pharm. Pat. Analyst 2012, 1, 285-299. (8) Fyfe, M. C. T.; McCormack, J. G.; Overton, H. A.; Procter, M. J.; Reynet, C. GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity. Expert Opin. Drug Discov. 2008, 3, 403-413. (9) Dhayal, S.; Morgan, N. G. The significance of GPR119 agonists as future treatment of type 2 diabetes. Drugs News Perspect. 2010, 23, 418-424. (10) Ohishi, T.; Yoshida, S. The therapeutic potential of GPR119 agonists for type 2 diabetes. Expert Opin. Investig. Drugs 2012, 21, 321-328. (11) Shah, U.; Edmondson, S.; Szewczyk, J. W. Recent advances in the discovery of GPR119 agonists. In New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches (RSC Drug Discovery Series No. 27); Jones, R. M., Ed.; The Royal Society of Chemistry, 2012; pp 177-214.


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Page 33 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(12) Cornall, L. M.; Mathai, M. L.; Hryciw, D. H.; McAinch, A. J. Is GPR119 agonism an appropriate treatment modality for the safe amelioration of metabolic diseases? Expert Opin. Investig. Drugs 2013, 22, 487-498. (13) Kang, S.-U. GPR119 agonists: a promising approach for T2DM treatment? A SWOT analysis of GPR119. Drug Discov. Today 2013, 18, 1309-1324. (14) Mo, X.-L.; Yang, Z.; Tao, Y.-X. Targeting GPR119 for the potential treatment of type 2 diabetes mellitus. Prog. Mol. Biol. Transl. Sci. 2014, 121, 95-131. (15) Zhu, X.; Huang, W.; Qian, H. GPR119 agonists: A novel strategy for type 2 diabetes treatment. In Diabetes Mellitus – Insights and Perspectives, 2013, InTech, DOI: 10.5772/48444, pp 59-82. (16) Polli, J. W.; Hussey, E.; Bush, M.; Generaux, G.; Smith, G.; Collins, D.; McMullen, S.; Turner, N.; Nunez, D. J. Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. Xenobiotica 2013, 43, 498-508. (17) Nunez, D. J.; Bush, M. A.; Collins, D.; McMullen, S. L.; Gillmor, D.; Apseloff, G.; Atiee, G.; Corsino, L.; Morrow, L.; Feldman, P. L. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: Results from two randomized studies. PLOS ONE 2014, 9, 1-15. (18) Semple, G.; Ren, A.; Fioravanti, B.; Pereira, G.; Calderon, I.; Choi, K.; Xiong, Y.; Shin, Y.-J.; Gharbaoui, T.; Sage, C. R.; Morgan, M.; Xing, C.; Chu, Z.-L.; Leonard, J. N.; Grottick, A. J.; Al-Shamma, H.; Liang, Y.; Demarest, K. T.; Jones, R. M. Discovery of fused bicyclic


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agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent model of glucose control. Bioorg. Med. Chem. Lett. 2011, 21, 3134-3141. (19) Semple, G.; Lehmann, J.; Wong, A.; Ren, A.; Bruce, M.; Shin, Y.-J.; Sage, C. R.; Morgan, M.; Chen, W.-C.; Sebring, K.; Chu, Z.-L.; Leonard, J. N.; Al-Shamma, H.; Grottick, A. J.; Du, F.; Liang, Y.; Demarest, K.; Jones, R. M. Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile. Bioorg. Med. Chem. Lett. 2012, 22, 1750-1755. (20) Katz, L. B.; Gambale, J. J.; Rothenberg, P. L.; Vanapalli, S. R.; Vaccaro, N.; Xi, L.; Polidori, D. C.; Vets, E.; Sarich, T. C.; Stein, P. P. Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects. Clin. Pharmacol. Ther. 2011, 90, 685-692. (21) Katz, L. B.; Gambale, J. J.; Rothenberg, P. L.; Vanapalli, S. R.; Vaccaro, N.; Xi, L.; Sarich, T. C.; Stein, P. P. Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes. Diabetes, Obes. Metabol. 2012, 14, 709-716. (22) Wacker, D. A.; Wang, Y.; Broekema, M.; Rossi, K.; O’Connor, S.; Hong, Z.; Wu, G.; Malmstrom, S. E.; Hung, C.-P.; LaMarre, L.; Chimalakonda, A.; Zhang, L.; Xin, L.; Cai, H.; Chu, C.; Boehm, S.; Zalaznick, J.; Ponticiello, R.; Sereda, L.; Han, S.-P.; Zebo, R.; Zinker, B.; Luk, C. E.; Wong, R.; Everlof, G.; Li, Y.-X.; Wu, C. K.; Lee, M.; Griffen, S.; Miller, K. J.; Krupinski, J.; Robl, J. A. Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119. J. Med. Chem. 2014, 57, 7499-7508.


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(23) He, Y.-L.; Zhang, Y.; Yan, J.-H.; Zhou, W.; Komjathy, S.; Taylor, A. High-quality triplicate electrocardiogram monitoring in a first-in-man study: Potential for early detection of drug -induced QT prolongation. Int. J. Clin. Pharmacol. Therap. 2013, 51, 948-957. (24) Overton, H. A.; Fyfe, M. C. T.; Reynet, C. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br. J. Pharmacol. 2008, 153, S76-S81. (25) Fredriksson, R.; Höglund, P. J.; Gloriam, D. E. I.; Lagerström, M. C.; Schiöth, H. B. Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett. 2003, 554, 381-388. (26) Odori, S.; Hosoda, K.; Tomita, T.; Fujikura, J.; Kusakabe, T.; Kawaguchi, Y.; Doi, R.; Takaori, K.; Ebihara, K.; Sakai, Y.; Uemoto, S.; Nakao, K. GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function. Metab. Clin. Exp. 2013, 62, 70-78. (27) Little, T. J.; Isaacs, N. J.; Young R. L.; Ott, R.; Nguyen, N. Q.; Rayner, C. K.; Horowitz, M.; Feinle-Bisset, C. Characterization of duodenal expression and localization of fatty acidsensing receptors in humans: relationships with body mass index. Am. J. Physiol.: Gastrointest. Liver Physiol. 2014, 307, G958-G967. (28) Chu, Z.-L.; Carroll, C.; Alfonso, J.; Gutierrez, V; He, H.; Lucman, A.; Pedraza, M.; Mondala, H.; Gao, H.; Bagnol, D.; Chen, R.; Jones, R. M.; Behan, D. P.; Leonard, J. A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release. Endocrinology 2008, 149, 2038-2047.


35


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 46

(29) Chu, Z.-L.; Jones, R. M.; He, H.; Carroll, C.; Gutierrez, V; Lucman, A.; Moloney, M.; Gao, H.; Mondala, H.; Bagnol, D.; Unett, D.; Liang, Y.; Demarest, K.; Semple, G.; Behan, D. P.; Leonard, J. A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 2007, 148, 2601-2609. (30) Soga, T.; Ohishi, T.; Matsui, T.; Saito, T.; Matsumoto, M.; Takasaki, J.; Matsumoto, S.; Kamohara, M.; Hiyama, H.; Yoshida, S.; Momose, K.; Ueda, Y.; Matsushime, H.; Kobori, M.; Furuichi, K. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein coupled receptor. Biochem. Biophys. Res. Commun. 2005, 326, 744-751. (31) Overton, H. A.; Babbs, A. J.; Doel, S. M.; Fyfe, M. C. T.; Gardner, L. S.; Griffin, G.; Jackson, H. C.; Procter, M. J.; Rasamison, C. M.; Tang-Christensen, M.; Widdowson, P. S.; Williams, G. M.; Reynet, C. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006, 3, 167-175. (32) Chu, Z.-L.; Carroll, C.; Chen, R.; Alfonso, J.; Gutierrez, V.; He, H.; Lucman, A.; Xing, C.; Sebring, K.; Zhou, J.; Wagner, B.; Unett, D.; Jones, R. M.; Behan, D. P.; Leonard, J. Noleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol. Endocrinol. 2010, 24, 161-170. (33) Syed, S. K.; Bui, H. H.; Beavers, L. S.; Farb, T. B.; Ficorilli, J.; Chesterfield, A. K.; Kuo, M.-S.; Bokvist, K.; Barrett, D. G.; Efanov, A. M. Regulation of GPR119 receptor activity with endocannabinoid-like lipids. Am. J. Physiol.: Endocrinol. Metabol. 2012, 303, E1469-E1478. (34) Hansen, H. S.; Rosenkilde, M. M.; Holst, J. J.; Schwartz, T. W. GPR119 as a fat sensor. Trends Pharmacol. Sci. 2012, 33, 374-381.


36

Page 37 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(35) Moran, B. M.; Abdel-Wahab, Y. H. A.; Flatt, P. R.; McKillop, A. M. Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice. Biol. Chem. 2014, 395, 453-464. (36) Kleberg, K.; Hassing, H. A.; Hansen, H. S. Classical endocannabinoid-like compounds and their regulation by nutrients. BioFactors 2014, 40, 363-372. (37) Zhu, X.; Huang, D.; Lan, X.; Tang, C.; Zhu, Y.; Han, J.; Huang, W.; Qian, H. The first pharmacophore model for potent G protein-coupled receptor 119 agonist. Eur. J. Med. Chem. 2011, 46, 2901-2907. (38) Semple, G.; Fioravanti, B.; Pereira, G.; Calderon, I.; Uy, J.; Choi, K.; Xiong, Y.; Ren, A.; Morgan, M.; Dave, V.; Thomsen, W.; Unett , D. J.; Xing, C.; Bossie, S.; Carroll, C.; Chu, Z.-L.; Grottick, A. J.; Hauser, E. K.; Leonard, J.; Jones, R. M. Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119. J. Med. Chem. 2008, 51, 51725175. (39) Buzard, D. J.; Kim, S. H.; Lehmann, J.; Han, S.; Calderon, I.; Wong, A.; Kawasaki, A.; Narayanan, S.; Bhat, R.; Gharbaoui, T.; Lopez, L.; Yue, D.; Whelan, K.; Al-Shamma, H.; Unett, D. J.; Shu, H.-H.; Tung, S.-F.; Chang, S.; Chuang, C.-F.; Morgan, M.; Sadeque, A.; Chu, Z.-L.; Leonard, J.; Jones, R. M. Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists. Bioorg. Med. Chem. Lett. 2014, 24, 4332-4335. (40) Katamreddy, S. R.; Carpenter, A. J.; Ammala, C. E.; Boros, E. E.; Brashear, R. L.; Briscoe, C. P.; Bullard, S. R.; Caldwell, R. D.; Conlee, C. R.; Croom, D. K.; Hart, S. M.; Heyer, D. O.; Johnson, P. R.; Kashatus, J. A.; Minick, D. J.; Peckham, G. E.; Ross, S. A.; Roller, S. G.; Samano, V. A.; Sauls, H. R.; Tadepalli, S. M.; Thompson, J. B.; Xu, Y.; Way, J. M. Discovery of


37


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 38 of 46

6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines as orally available G protein-coupled receptor 119 agonists. J. Med. Chem. 2012, 55, 10972-10994. (41) Gillespie, P.; Goodnow Jr., R. A.; Saha, G.; Bose, G.; Moulik, K.; Zwingelstein, C.; Myers, M.; Conde-Knape, K.; Pietranico-Cole, S.; So, S.-S. Discovery of pyrazolo[3,4d]pyrimidine derivatives as GPR119 agonists. Bioorg. Med. Chem. Lett. 2014, 24, 949-953. (42) Fevig, J. M.; Wacker, D. A. [6,5]-bicyclic GPR119 G protein-coupled receptor agonists WO 2008/137436, 2008. (43) Fevig, J. M.; Wacker, D. A. [6,6] and [6,7]-bicyclic GPR119 G protein-coupled receptor agonists. WO 2008/137435, 2008. (44) Neelamkavil, S. F.; Boyle, C. D.; Harris, J. M.; Stamford, A. W.; Hao, J.; Neustadt, B. R.; Chackalamannil, S.; Xia, Y., Greenlee, W. J. Bicyclic heterocycle derivatives and their use as GPCR modulators. WO 2010/009207, 2010. (45) Sato, K.; Sugimoto, H.; Rikimaru, K.; Imoto, H.; Kamaura, M.; Negoro, N.; Tsujihata, Y.; Miyashita, H.; Odani, T.; Murata, T. Discovery of a novel series of indoline carbamate and indolinylpyrimidine derivatives as potent GPR119 agonists. Bioorg. Med. Chem. 2014, 22, 16491666. (46) McClure, K. F.; Darout, E.; Guimarães, C. R. W.; DeNinno, M. P.; Mascitti, V.; Munchhof, M. J.; Robinson, R. P.; Kohrt, J.; Harris, A. R.; Moore, D. E.; Li, B.; Samp, L.; Lefker, B. A.; Futatsugi, K.; Kung, D.; Bonin, P. D.; Cornelius, P.; Wang, R.; Salter, E.; Hornby, S.; Kalgutkar, A. S.; Chen, Y. Activation of the G-protein-coupled receptor 119: A


38

Page 39 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


conformation-based hypothesis for understanding agonist response. J. Med. Chem. 2011, 54, 1948-1952. (47) Darout, E.; Robinson, R. P.; McClure, K. F.; Corbett, M.; Li, B.; Shavnya, A.; Andrews, M. P.; Jones, C. S.; Li, Q.; Minich, M. L.; Mascitti, V.; Guimarães, C. R. W.; Munchhof, M. J.; Bahnck, K. B.; Cai, C.; Price, D. A.; Liras, S.; Bonin, P. D.; Cornelius, P.; Wang, R.; Bagdasarian, V.; Sobota, C. P.; Hornby, S.; Masterson, V. M.; Joseph, R. M.; Kalgutkar, A. S.; Chen, Y. Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119. J. Med. Chem. 2013, 56, 301-319. (48) Xia, Y.; Chackalamannil, S.; Greenlee, W. J.; Jayne, C.; Neustadt, B.; Stamford, A.; Vaccaro, H.; Xu, X.; Baker, H.; O’Neill, K.; Woods, M.; Hawes, B.; Kowalski, T. Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes. Bioorg. Med. Chem. Lett. 2011, 21, 3290-3296. (49) Pham, T.-A. N.; Yang, Z.; Fang, Y.; Luo, J.; Lee, J.; Park, H. Synthesis and biological evaluation of novel 2,4-disubstituted quinazoline analogues as GPR119 agonists. Bioorg. Med. Chem. 2013, 21, 1349-1356. (50) Yang, Z.; Fang, Y.; Pham, T.-A. N.; Lee, J.; Park, H. Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents as GPR119 agonists. Bioorg. Med. Chem. Lett. 2013, 23, 1519-1521. (51) Scott, J. S.; Birch, A. M.; Brocklehurst, K. J.; Broo, A.; Brown, H. S.; Butlin, R. J.; Clarke, D. S.; Davidsson, Ö.; Ertan, A.; Goldberg, K.; Groombridge, S. D.; Hudson, J. A.; Laber, D.; Leach, A. G.; MacFaul, P. A.; McKerrecher, D.; Pickup, A.; Schofield, P.; Svensson, P. H.; Sörme, P.; Teague, J. Use of small-molecule crystal structures to address solubility in a novel


39


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Page 40 of 46

series of G protein-coupled receptor 119 agonists: Optimization of a lead and in vivo evaluation. J. Med. Chem. 2012, 53, 5361-5379. (52) Brocklehurst, K. J.; Broo, A.; Butlin, R. J.; Brown, H. S.; Clarke, D. S.; Davidsson, Ö.; Goldberg, K.; Groombridge, S. D.; Kelly, E. E.; Leach, A.; McKerrecher, D.; O’Donnell, C.; Poucher, S.; Schofield, P. Scott, J. S.; Teague, J.; Westgate, L.; Wood, M. J. M. Discovery, optimisation and in vivo evaluation of novel GPR119 agonists Bioorg. Med. Chem. Lett. 2011, 21, 7310-7316. (53) Scott, J. S.; Bowker, S. S.; Brocklehurst, K. J.; Brown, H. S.; Clarke, D. S.; Easter, A.; Ertan, A.; Goldberg, K.; Hudson, J. A.; Kavanagh, S.; Laber, D.; Leach, A. G.; MacFaul, P. A.; Martin, M. A.; McKerrecher, D.; Schofield, P.; Svensson, P. H.; Teague, J. Circumventing seizure activity in a series of G protein-coupled receptor 119 (GPR119) agonists. J. Med. Chem. 2014, 57, 8984-8998. (54) Scott, J. S.; Birch, A. M.; Brocklehurst, K. J.; Brown, H. S.; Goldberg, K.; Groombridge, S. D.; Hudson, J. A.; Leach, A. G.; MacFaul, P. A.; McKerrecher, D.; Poultney, R.; Schofield, P.; Svensson, P. H. Optimisation of aqueous solubility in a series of G protein-coupled receptor 119 (GPR119) agonists. Med. Chem. Comm. 2013, 4, 95-100. (55) Scott, J. S.; Brocklehurst, K. J.; Brown, H. S.; Clarke, D. S.; Coe, H.; Groombridge, S. D.; Laber, D.; MacFaul, P. A.; McKerrecher, D.; Schofield, P. Conformational restriction in a series of GPR119 agonists: Differences in pharmacology between mouse and human. Bioorg. Med. Chem. Lett. 2013, 23, 3175-3179. (56) Sakairi, M.; Kogami, M.; Torii, M.; Kataoka, H.; Fujieda, H.; Makino, M.; Kataoka, D.; Okamoto, R.; Miyazawa, T.; Okabe, M.; Inoue, M.; Takahashi, N.; Harada, S.; Watanabe, N.


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Synthesis and SAR studies of bicyclic amine series GPR119 agonists. Bioorg. Med. Chem. Lett. 2012, 22, 5123-5128. (57) Sakairi, M.; Kogami, M.; Torii, M.; Kuno, Y.; Ohsawa, Y.; Makino, M.; Kataoka, D.; Okamoto, R.; Miyazawa, T.; Inoue, M.; Takahashi, N.; Harada, S.; Watanabe, N. Synthesis and biological evaluation of a 6-aminofuro[3,2-c]pyridin-3(2H)-one series of GPR 119 agonists. Arzneimittelforschung 2012, 62, 537-544. (58) Sakairi, M.; Kogami, M.; Torii, M.; Makino, M.; Kataoka, D.; Okamoto, R.; Miyazawa, T.; Inoue, M.; Takahashi, N.; Harada, S.; Watanabe, N. Synthesis and pharmacological profile of a new selective G protein-coupled receptor 119 agonist; 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one. Chem. Pharm. Bull. 2012, 60, 1093-1095. (59) Wellenzohn, B.; Lessel, U.; Beller, A.; Isambert, T.; Hoenke, C.; Nosse, B. Identification of new potent GPR119 agonists by combining virtual screening and combinatorial chemistry. J. Med. Chem. 2012, 55, 11031-11041. (60) Ye, X.-Y.; Morales, C. L.; Wang, Y.; Rossi, K. A.; Malmstrom, S. E.; Abousleiman, M.; Sereda, L.; Apedo, A.; Robl, J. A.; Miller, K. J.; Krupinski, J.; Wacker, D. A. Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists. Bioorg. Med. Chem. Lett. 2014, 24, 2539-2545. (61) Koshizawa, T.; Hosoi, H.; Watanabe, G.; Morimoto, T.; Ohgiya, T.; Shibuya, K. A practical synthesis of (4-(spiro[chromane-2,4'-piperidin]-6-yl)phenyl)methanol as a key intermediate of novel GPR119 agonist. Heterocycles 2014, 89, 1632-1643.


41


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 42 of 46

(62) Koshizawa, T.; Yamazaki, Y.; Ohgiya, T.; Shibuya, K. A facile method for converting alcohol to thioether and its application in the synthesis of a novel GPR119 agonist. Tetrahedron 2015, 71, 3231-3236. (63) Szewczyk, J. W.; Acton, J.; Adams, A. D.; Chicchi, G.; Freeman, S.; Howard, A. D.; Huang, Y.; Li, C.; Meinke, P. T.; Mosely, R.; Murphy, E.; Samuel, R.; Santini, C.; Yang, M.; Zhang, Y.; Zhao, K.; Wood, H. B. Design of potent and selective GPR119 agonists for type II diabetes. Bioorg. Med. Chem. Lett. 2011, 21, 2665-2669. (64) Lohani, S.; Cooper, H.; Jin, X.; Nissley, B. P.; Manser, K.; Rakes, L. H.; Cummings, J. J.; Fauty, S. E.; Bak, A. Physicochemical properties, form, and formulation selection strategy for a biopharmaceutical classification system class II preclinical drug candidate. J. Pharm. Sci. 2014, 103, 3007-3021. (65) Leung, D. H.; Lohani, S.; Ball, R. G.; Canfield, N.; Wang, Y.; Rhodes, T.; Bak, A. Two novel pharmaceutical cocrystals of a development compound – screening, scale-up, and characterization. Cryst. Growth Des. 2012, 12, 1254-1262. (66) Leung, D. H.; Lamberto, D. J.; Liu, L.; Kwong, E.; Nelson, T.; Rhodes, T.; Bak, A. A new and improved method for the preparation of drug nanosuspension formulations using acoustic mixing technology. Int. J. Pharm. 2014, 473, 10-19. (67) Liu, P.; Hu, Z.; DuBois, B. G.; Moyes, C. R.; Hunter, D. N.; Zhu, C.; Kar, N. F.; Zhu, Y.; Garfunkle, J.; Kang, L.; Chicchi, G.; Ehrhardt, A.; Woods, A.; Seo, T.; Woods, M.; van Heek, M.; Dingley, K. H.; Pang, J.; Salituro, G. M.; Powell, J.; Terebetski, J. L.; Hornak, V.; Campeau, L.-C.; Lamberson, J.; Ujjainwalla, F.; Miller, M.; Stamford, A.; Wood, H. B.; Kowalski, T.;


42

Page 43 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Nargund, R. P.; Edmondson, S. D. Design of potent and orally active GPR119 agonists for the treatment of type II diabetes. ACS Med. Chem. Lett. 2015, 6, 936-941. (68) Han, S.; Narayanan, S.; Kim, S. H.; Calderon, I.; Zhu, X.; Kawasaki, A.; Yue, D.; Lehmann, J.; Wong, A.; Buzard, D. J.; Semple, G.; Carrol, C.; Chu, Z.-L.; Al-Sharmma, H.; Shu, H.-H.; Tung, S.-F.; Unett, D. J.; Behan, D. P.; Yoon, W. Y.; Morgan, M.; Usmani, K. W.; Chen, C.; Sadeque, A.; Leonard, J. N.; Jones, R. M. Discovery of novel trans-1,4-dioxycyclo-hexane GPR119 agonist series. Bioorg. Med. Chem. Lett. 2015, 25, 3034-3038. (69) Futatsugi, K.; Mascitti, V.; Guimarães, C. R. W.; Morishita, N.; Cai, C.; DeNinno, M. P.; Gao, H.; Hamilton, M. D.; Hank, R.; Harris, A. R.; Kung, D. W.; Lavergne, S. Y.; Lefker, B. A.; Lopaze, M. G.; McClure, K. F.; Munchhof, M. J.; Preville, C.; Robinson, R. P.; Wright, S. W.; Bonin, P. D.; Cornelius, P.; Chen, Y.; Kalgutkar, A. S. From partial to full agonism: Identification of a novel 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole as a full agonist of the human GPR119 receptor. Bioorg. Med. Chem. Lett. 2013, 23, 194-197. (70) Yoshida, S.; Ohishi, T.; Matsui, T.; Shibasaki, M. Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion. Biochem. Biophys. Res. Commun. 2010, 400, 437-441. (71) Negoro, K.; Yonetoku, Y.; Maruyama, T.; Yoshida, S.; Takeuchi, M.; Ohta, M. Synthesis and structure–activity relationship of 4-amino-2-phenylpyrimidine derivatives as a series of novel GPR119 agonists. Bioorg. Med. Chem. 2012, 20, 2369-2375. (72) Yoshida, S.; Ohishi, T.; Matsui, T.; Tanaka, H.; Oshima, H.; Yonetoku, Y.; Shibasaki, M. Novel GPR119 agonist AS1535907 contributes to first-phase insulin secretion in rat perfused pancreas and diabetic db/db mice. Biochem. Biophys. Res. Commun. 2010, 402, 280-285.


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(73) Oshima, H.; Yoshida, S.; Ohishi, T.; Matsui, T.; Tanaka, H.; Yonetoku, Y.; Shibasaki, M.; Uchiyama, Y. Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice. Life Sciences 2013, 92, 167173. (74) Negoro, K.; Yonetoku, Y.; Misawa-Mukai, H.; Hamaguchi, W.; Maruyama, T.; Yoshida, S.; Takeuchi, M.; Ohta, M. Discovery and biological evaluation of novel 4-amino-2phenylpyrimidine derivatives as potent and orally active GPR119 agonists. Bioorg. Med. Chem. 2012, 20, 5235-5246. (75) Negoro, K.; Yonetoku, Y.; Moritomo, A.; Hayakawa, M.; Iikubo, K.; Yoshida, S.; Takeuchi, M.; Ohta, M. Synthesis and structure–activity relationship of fused-pyrimidine derivatives as a series of novel GPR119 agonists. Bioorg. Med. Chem. 2012, 20, 6442-6451. (76) Zhang, J.; Li, A.-R.; Yu, M.; Wang, Y.; Zhu, J.; Kayser, F.; Medina, J. C.; Siegler, K.; Conn, M.; Shan, B.; Grillo, M. P.; Eksterowicz, J.; Coward, P.; Liu, J. Discovery and optimization of arylsulfonyl 3-(pyridin-2-yloxy)anilines as novel GPR119 agonists. Bioorg. Med. Chem. Lett. 2013, 23, 3609-3613. (77) Wang, Y.; Yu, M.; Zhu, J.; Zhang, J.; Kayser, F.; Medina, J. C.; Siegler, K.; Conn, M.; Shan, B.; Grillo, M. P.; Liu, J.; Coward, P. Discovery and optimization of 5-(2-((1(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel GPR119 agonists. Bioorg. Med. Chem. Lett. 2014, 24, 1133-1137. (78) Yu, M.; Zhang, J.; Wang, Y.; Zhu, J.; Kayser, F.; Medina, J. C.; Siegler, K.; Conn, M.; Shan, B.; Grillo, M. P.; Coward, P.; Liu, J. Discovery and optimization of N-(3-(1,3-dioxo-2,3-


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dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamides

as

novel

GPR119

agonists. Bioorg. Med. Chem. Lett. 2014, 24, 156-160. (79) Mascitti, V.; Stevens, B. D.; Choi, C.; McClure, K. F.; Guimarães, C. R. W.; Farley, K. A.; Munchhof, M. J.; Robinson, R. P.; Futatsugi, K.; Lavergne, S. Y.; Lefker, B. A.; Cornelius, P.; Bonin, P. D.; Kalgutkar, A. S.; Sharma, R.; Chen, Y. Design and evaluation of a 2-(2,3,6trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. Bioorg. Med. Chem. Lett. 2011, 21, 1306-1309. (80) Alper, P.; Azimioara, M.; Cow, C.; Mutnick, D.; Nikulin, V.; Michellys, P.-Y.; Wang, Z.; Reding, E.; Paliotti, M.; Li, J.; Bao, D.; Zoll, J.; Kim,Y.; Zimmerman, M.; Groessel, T.; Tuntland, T.; Joseph, S. B.; McNamara, P.; Seidel, H. M.; Epple, R. Discovery of structurally novel, potent and orally efficacious GPR119 agonists. Bioorg. Med. Chem. Lett. 2014, 24, 23832387. (81) Azimioara, M.; Alper, P.; Cow, C.; Mutnick, D.; Nikulin, V.; Lelais, G.; Mecom, J.; McNeill, M.; Michellys, P.-Y.; Wang, Z.; Reding, E.; Paliotti, M.; Li, J.; Bao, D.; Zoll, J.; Kim, Y.; Zimmerman, M.; Groessl, T.; Tuntland, T.; Joseph, S. B.; McNamara, P.; Seidel, H. M.; Epple, R. Novel tricyclic pyrazalopyrimidines as potent and selective GPR119 agonists. Bioorg. Med. Chem. Lett. 2014, 24, 5478-5483.


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TABLE OF CONTENTS GRAPHIC


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G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment

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