Discovery of 2-Pyridylureas as Glucokinase Activators - American

Sep 9, 2014 - Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States. ‡. Amgen, Inc., 1120 Veterans Boulevard, South San ...
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Discovery of 2‑Pyridylureas as Glucokinase Activators Ronald J. Hinklin,*,† Thomas D. Aicher,†,§ Deborah A. Anderson,† Brian R. Baer,† Steven A. Boyd,†,∥ Kevin R. Condroski,†,⊥ Walter E. DeWolf, Jr.,† Christopher F. Kraser,† Maralee McVean,†,# Susan P. Rhodes,† Hillary L. Sturgis,† Walter C. Voegtli,†,∞ Lance Williams,† and Jonathan B. Houze‡ †

Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States

‡

S Supporting Information *

ABSTRACT: Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.

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INTRODUCTION Type 2 diabetes is a chronic, progressive metabolic disease typically characterized by hyperglycemia, hyperlipidemia, and insulin resistance. In 2007, type 2 diabetes affected an estimated 270 million people worldwide and is anticipated to exceed 360 million before 2030 because of the increasing age, sedentary lifestyle, and incidence of obesity in the global population.1 Despite the introduction of new antihyperglycemic agents in recent years, there exists a need for more effective therapies for type 2 diabetes.2 We selected glucokinase3 activation as a promising strategy to address many of these goals.4−6 Glucokinase is a member of the hexokinase family of cellular enzymes that are responsible for the conversion of glucose to glucose 6-phosphate, the first step in glucose utilization. It is the rate-limiting enzyme in glucose-stimulated insulin secretion in the pancreas. In the liver, glucokinase attenuates glucose utilization, storage, and production. Scientists at Hoffmann-La Roche were the first to describe small molecule activators of glucokinase.7 Subsequently, GKAs were disclosed by many other groups.8 The discovery effort at Array BioPharma resulted in the identification of ARRY-403, which was subsequently licensed to Amgen to become AMG 151.9 Compounds 1−5 (Figure 1) are a selection of GKAs that have progressed into phase II clinical trials and contain similar key pharmacophores, highlighted in blue.10 The unique thiadiazole-aminopyridine core of GKA23 (6)11 was designed so that the conserved bidentate hydrogen bond to Arg63 remained, along with access to the hydrophobic pockets of the allosteric binding site. In the pursuit of alternative templates, an idea that was investigated was to replace the aminothiadiazole with a urea to maintain the hydrogen bond network. In this report, we will discuss the initial efforts of this investigation which resulted in the identification of pyridylureas as a novel bidentate hydrogen bonding motif for GKAs. © XXXX American Chemical Society

CHEMISTRY The chemistry to access various pyridylureas is shown in Scheme 1. Selective displacement of the nitro or fluoro group from the commercially available cyanopyridines 7a and 7b, respectively, with various phenols afforded 8a−d.12 The more reactive 7b was utilized for the synthesis of 8c because of the poor nucleophilicity of the hydroxypyrazole. Subsequent SNAr reaction with pyridine-2-thiol afforded the 3,5-disubstituted cyanopyridines 9a−d. Acid hydrolysis of the nitrile to the corresponding primary amides 10a−d, followed by Hofmann rearrangement, yielded the key aminopyridines 11a−d. Acylation of the aminopyridines under a variety of conditions gave compounds 12a−15a as an initial exploration for active motifs. Compounds 16a−25a were synthesized in order to determine the tolerance for substitution of the urea. Substitution at the 3-position of the pyridine core was explored with compounds 16a−d. Investigation of the substitution at the 5-position of the pyridine core was achieved via the route in Scheme 2. In this case, the 2- and 3-position substitutions were held constant as methylurea and 2-methyl-3-pyridyl, respectively. The 5-bromo2-cyanopyridine 8b was hydrolyzed to the amide 26 followed by Hofmann rearrangement to the aminopyridine 27. The methylurea was incorporated via activation with p-nitrophenyl chloroformate, followed by attack with methylamine to afford the intermediate 28.13 The first set of 5-SR derivatives was synthesized via a latent thiolate approach. Palladium-mediated incorporation of methyl 3-mercaptopropanoate afforded 29, which was β-eliminated with potassium tert-butoxide to the thiolate anion and subsequently quenched with various electrophiles to afford thioethers 30−34.14 Alternatively, direct Received: August 5, 2014

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Figure 1. Various GKAs that have progressed into clinical trials (1−5). The conserved amide−amino heterocycle present in a majority of the known GKAs is absent in GKA23 (6).

Scheme 1. Synthesis of Carbonyl Substituted Aminopyridinesa

a

Reagents and conditions: (a) ROH, K2CO3, DMF or NMP; (b) ROH, NaH, DMF:dioxane; (c) 2-Pyr-SH, NaH, DMF; (d) conc HCl; (e) NBS, KOH, MeOH or Br2, KOH, dioxane; (f) HCO2H, Ac2O or AcCl or ClCO2Et or R′NCO or (i) ClCO2-p-NO2-Ph; (ii) R′-NH2.

In addition to our standard EC50 enzyme assay, two other assays that we used routinely were the 4% human serum albumin shifted EC50 (4% HSA) and a maximal velocity assay (Vmax) (see Supporting Information). The 4% HSA-shifted assay was utilized as a higher throughput surrogate for plasma protein binding, and fold-shifts of 50000 >50000 203 88 1730 >50000 2120 1620 758 952 393 276 172

41400 N/A N/A 547 231 4480 N/A 2840 3990 1970 1160 5850 2830 1530

104 N/A N/A 64 77 77 N/A 66 72 75 73 84 68 66

Figure 2. Protein crystal structure of 16a showing a bidentate hydrogen bond to Arg63 and an internal hydrogen bond of the urea to the pyridine.

conformation, with the distal NH of the urea participating in an internal hydrogen bond with the pyridine core. This allows for the critical donor/acceptor hydrogen bonds to Arg63. The ethyl pyridyl ether on the 3-position of the pyridyl core sits in a pocket with the ethyl group pointing back toward a number of hydrophobic residues. The 5-position thiopyridyl group also fills its cavity well. This particular cavity, however, is known to be tolerant of a wide variety of shapes and functionalities by induced fit.8 Shown in Table 2 are results of the investigation into the 3 and 5 positions of the core pyridine. At the 3-position, three other heteroaryl ether derivatives were investigated based on docking results (16a−d). None of these derivatives were more potent than the initial 2-ethylpyridyl group. However, the ethylpyrazole 16c did provide a boost in Vmax to 90%, which was above the desired threshold. When considering the in vitro metabolic stability of these derivatives, the methylpyridine 16b was selected to remain constant while investigating SAR changes at the 5-position.

a

The variability of each of the parameters was estimated based on the historical performance of a reference compound. The estimated coefficients of variation for the EC50, 4% HSA EC50, and Vmax are 30% (n = 383), 32% (n = 90), and 4% (n = 329), respectively. bAssay run at 5 mM glucose.

improve potency and/or physical properties. Contrary to our expectations, the most potent derivative was the simple methylurea 16a. Addition of anything larger or smaller than a methyl group resulted in decreases in the potency, and usually the Vmax, of the GKA. Consequently, our work focused on the methylurea moiety for the majority of this investigation. To confirm the predicted binding mode, 16a was cocrystallized with GK. As can be seen in Figure 2, the aryl NH and carbonyl of the urea are orientated in the desired s-cis C

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Table 2. Modification of 3- and 5-Positions of Pyridylurea Glucokinase Activatorsa

a

The variability of each of the parameters was estimated based on the historical performance of a reference compound. The estimated coefficients of variation for the EC50, 4% HSA EC50, and Vmax are 30% (n = 383), 32% (n = 90), and 4% (n = 329), respectively.

with 33, the significant decrease in Vmax precluded these compounds from being advanced. Compound 33 was selected for predictive in vitro ADME assays. As shown in Figure 3, 33 has good solubility at neutral

Changes to the S-2-Pyr group at the 5-position of the core pyridine were also investigated. While displaying adequate enzymatic activities, the biaryl thioether did not provide for acceptable physical properties (CLogP, solubility) or microsomal extraction ratios. Many changes were made to the thioether group (30−38) in an attempt to address these issues. Insertion of a methylene between the sulfur and the pyridine to afford 30 reduced the potency by approximately 10-fold. However, this change doubled the Vmax to 146%, which is more desirable. Changing the polar pyridine to a phenyl group (31) recovered the potency, but the Vmax dropped below our target, and the microsomal clearance was very high. Attempts at lowering the lipophilicity of these compounds were investigated with 32 and 33. These compounds displayed reasonable potency, with less than 2-fold plasma protein EC50 shifts. Notably, 33 had Vmax that was in the acceptable range, and by lowering the CLogP below 3.0, the in vitro microsomal extraction ratio was also significantly improved. Variations of the thioether chain of 33 were investigated as a potential area of potency enhancement. By locking out a number of rotatable bonds in the correct manner, an increase in potency was anticipated. With 34 and 35, this was not achieved; however, the potency was not lost either. Further lowering of the CLogP was achieved with 37 and 38. While equipotent

Figure 3. In vitro characteristics of 33, showing advantageous properties suitable for progressing into in vivo studies.

pH, high permeability with no significant P-gp efflux, and nearly 40% free compound in a human plasma protein binding study. Analysis of these in vitro properties showed that 33 had a high likelihood of obtaining efficacious free drug concentrations, for an extended period of time, at a reasonable dose and was chosen to proceed into in vivo studies. 33 was evaluated in a mouse pharmacokinetic study following both iv and po dosing. The observed clearance (iv, 1 mg/kg) in fed male CD-1 mice was low (Table 3), consistent D

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glucose tolerance test for any tested animal, n = 8) for the 30 mg/kg dose was 73 mg/dL. 33 was evaluated in a 14 day study in ob/ob mice. After 14 days of dosing at 3, 30, and 100 mg/kg b.i.d., the 30 and 100 mg/kg doses lowered the glucose excursion in an OGTT (Figure 5). Compound 33 at 100 mg/kg also significantly lowered fasting blood glucose (125.9 vs 187.9 mg/dL, p = 0.02). In summary, we have developed a new core scaffold for GKAs. This new scaffold has allowed for the generation of GKAs with low molecular weight and beneficial physical properties, such as CLogP and solubility. Compound 33 was a very intriguing early compound in this series. Additional modifications were made to identify potential backup clinical candidates, which will be disclosed at a later date.

Table 3. Pharmacokinetics of 33 in Mice after a Single 1 mg/ kg iv or 10 mg/kg po Dose 1 mg/kg iv 40% PEG400/20% EtOH /40% saline (v/v, solution)

10 mg/kg po aqueous 1% CMC/0.05% Tween 80 (w/v, suspension)

parametera

valueb

parametera

valueb

AUClast (h·μg/mL) AUCinf (h·μg/mL) CL (mL min−1 kg−1) ER (%)c t1/2 (h) VSS (L/kg)

0.762 0.773 21.5 23.9 2.67 1.98

AUClast (h·μg/mL) AUCinf (h·μg/mL) Cmax (μg/mL) Tmax (h) F (%)

5.03 5.24 2.32 0.500 67.8

a

Parameter abbreviations: AUC (area under the curve, calculated to the last measurable time point or to infinity); CL (clearance); VSS (steady-state volume); ER (extraction ratio); Cmax (maximum observed concentration); Tmax (time of the maximum observed plasma concentration); F (bioavailability). bValues are calculated from arithmetic mean plasma concentrations (n = 3/(time point)). cER was calculated using a value of 90 mL min−1 kg−1 for mouse hepatic blood flow.

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EXPERIMENTAL SECTION

Chemistry. Commercially available reagents and solvents were used without further purification. Nuclear magnetic resonance (NMR) spectra were measured in the indicated solvent with tetramethylsilane (TMS) or the residual solvent peak as the internal standard on a Varian 400 MHz spectrometer. Chemical shifts (δ) are in parts per million. LC−MS experiments were performed on an Agilent 1100 HPLC coupled with an Agilent MSD mass spectrometer using APCI as ionization source. Peaks were detected by UV absorbance at 220 and 254 nm, and MS full scan was applied to all experiments. All compounds disclosed in this paper were confirmed to be >95% purity via this method. 5-Bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (8b). 5Bromo-3-nitropicolinonitrile (45.4 g, 199 mmol) was dissolved in DMF (200 mL) and stirred at room temperature until dissolved. 2Methylpyridin-3-ol (22.8 g, 209 mmol) was added and stirred until dissolved. Water (30 mL) was added followed by K2CO3 (27.5 g, 199 mmol) and the mixture stirred at room temperature for 2 h. The mixture was slowly poured into water (1 L), stirred for 20 min, filtered, and dried in a vacuum oven to afford 5-bromo-3-(2-methylpyridin-3yloxy)picolinonitrile (55.5 g, 191 mmol, 96.1% yield). 1H NMR (CDCl3) δ ppm 8.52 (dd, J = 4.7, 1.4 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.2, 1.4 Hz, 1H), 7.27 (dd, J = 8.2, 4.7 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 2.50 (s, 3H); MS (APCI) m/e 290.1, 292.1 (M + H)+. 5-Bromo-3-(2-methylpyridin-3-yloxy)picolinamide (26). 12 M HCl (35 mL) was cooled to −10 °C in an ice−EtOH bath, and to the cooled liquid was added 5-bromo-3-(2-methylpyridin-3yloxy)picolinonitrile (2.25 g, 7.8 mmol). The mixture stirred until a solution was obtained. The ice bath was removed, and the mixture was stirred overnight at room temperature. To the mixture was added ice,

with the clearance predicted by the stability in mouse liver microsomes (22 vs 31 mL min−1 kg−1). Dosing of 33 at 10 mg/ kg po as a suspension in 1% carboxymethylcellulose (CMC) and 0.05% Tween 80 resulted in good bioavailability in mice (F = 67.8%; Table 3), and the plasma concentrations exceeded the 4% HSA protein-adjusted EC50 for approximately 6 h. The results from the oral PK study in CD-1 mice warranted further efficacy studies in animal models of type 2 diabetes. Compound 33 was progressed into a dose−response oral glucose tolerance test (OGTT) in C57BL/6 mice. On the basis of the plasma concentrations in the PK study being above the plasma-shifted EC50 for approximately 6 h, it was predicted that a 10 mg/kg dose would be efficacious. A lower (3 mg/kg) and higher dose (30 mg/kg) was incorporated in an attempt to observe a minimally and maximally efficacious dose. Mean concentrations of 33 in plasma at 2.5 h postdose (n = 8/dose group) were 0.046, 0.178, and 0.633 μg/mL (or 41%, 158%, and 562% of the 4% HSA protein-adjusted EC50) following the 3, 10, and 30 mg/kg doses, respectively. As can be seen in Figure 4, the 10 and 30 mg/kg doses were equally efficacious in terms of AUC lowering (28.8% vs 30.8%). One observation that was encouraging was that the glucosemin (the lowest glucose concentration observed at the 2 h time point in the oral

Figure 4. Dose response OGTT of 33 in C57/Bl/6 mice. The AUC reductions for the 3, 10, and 30 mg/kg doses were 8.0%, 28.6%*, and 30.8%*, respectively. (* denotes p < 0.05). E

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Figure 5. Day 14 OGTT in ob/ob mice. At a dose of 100 mg/kg, fasting blood glucose (−0.5 h) and excursion were effectively lowered. The AUC reductions for the 3, 30, and 100 mg/kg doses were 18.4%, 33.3%*, and 30.8%*, respectively. (* denotes p < 0.05). and a 30% NaOH solution was added slowly, keeping the temperature below 20 °C during the base addition to adjust the pH of the mixture to 12. The mixture was then extracted with EtOAc, washed with brine, dried over MgSO4 , and evaporated to afford 5-bromo-3-(2methylpyridin-3-yloxy)picolinamide (2.20 g, 7.14 mmol, 92% yield) as a white solid. 1H NMR (CDCl3) δ ppm 8.44−8.33 (m, 2H), 7.55 (s, 1H), 7.28 (m, 1H), 7.23−7.17 (m, 2H), 5.90 (s, 1H), 2.53 (s, 3H); MS (APCI) m/e 308.0, 310.0 (M + H)+. 5-Bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (27). 5-Bromo-3-(2-methylpyridin-3-yloxy)picolinamide (44.70 g, 145.1 mmol) was dissolved in MeOH (200 mL) and cooled in an ice bath. 1-Bromopyrrolidine-2,5-dione (33.57 g, 188.6 mmol) was added, followed by water (22 mL). Potassium hydroxide (41.75 g, 744.2 mmol) in water (42 mL) was added slowly and stirred at room temperature overnight. The mixture was then heated to 65 °C for 24 h. The reaction was cooled to room temperature, diluted with water (25 mL), filtered, and dried to afford 5-bromo-3-(2-methylpyridin-3yloxy)pyridin-2-amine (36.6 g, 169 mmol, 90.0% yield). 1H NMR (CDCl3) δ ppm 8.39 (dd, J = 4.5, 1.6 Hz, 1H), 7.90 (d J = 2.0 Hz, 1H), 7.22 (dd J = 8.2, 1.8 Hz, 1H), 7.18 (dd J = 8.2, 4.5 Hz, 1H), 6.86 (d J = 2.0 Hz, 1H), 4.82 (br s, 2H), 2.51 (s, 3H); MS (APCI) m/e 280.1, 282.1 (M + H)+. 1-(5-Bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3methylurea (28). 5-Bromo-3-(2-methylpyridin-3-yloxy)pyridin-2amine (10.0 g, 35.7 mmol) was dissolved in CH2Cl2 (100 mL), and pyridine (8.64 mL, 107 mmol) was added. 4-Nitrophenyl carbonochloridate (14.4 g, 71.4 mmol) was added in portions and allowed to stir at room temperature for 1 h. 33% MeNH2 in EtOH (44.8 mL, 357 mmol) was carefully added and the mixture stirred at room temperature overnight. The mixture was poured into 1 N NaOH, extracted with CH2Cl2, washed with 1 N NaOH, dried over sodium sulfate, filtered, and concentrated. The residue was purified over silica gel (1−3% MeOH in EtOAc) to afford 1-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (7.00 g, 20.8 mmol, 58.2% yield) as a tan solid. 1H NMR (CDCl3) δ ppm 8.95 (m, 1H), 8.47 (dd, J = 4.5, 1.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.31−7.21 (m, 2H), 6.86 (d, J = 2.0 Hz, 1H), 2.99 (d, J = 4.7 Hz, 3H), 2.46 (s, 3H); MS (APCI) m/e 336.9, 338.9 (M + H)+. Methyl 3-(5-(2-Methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (29). 1-(5-Bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (4.40 g, 13.0 mmol) was dissolved in dioxane (100 mL), and N-ethyl-N-isopropylpropan-2amine (4.55 mL, 26.1 mmol) and Xantphos (0.378 g, 0.652 mmol) were added. The solution was bubbled through with nitrogen for 10 min. Pd2dba3 (0.299 g, 0.326 mmol) and methyl 3-mercaptopropanoate (1.55 mL, 14.4 mmol) were added, and the mixture was plunged into a 90 °C oil bath for 1.5 h. The mixture was cooled to room temperature, filtered through Celite, concentrated, and purified over silica gel (5% MeOH in EtOAc) to afford methyl 3-(5-(2-

methylpyridin-3-yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (4.10 g, 10.9 mmol, 83.5% yield). 1H NMR (CDCl3) δ ppm 9.10 (m, 1H), 8.44 (dd, J = 4.6, 1.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.51 (s, 1H), 7.25 (dd, J = 8.2, 1.4 Hz, 1H), 7.21 (dd, J = 8.2, 4.5 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 3.64 (s, 3H), 3.01−2.94 (m, 5H), 2.52 (t, J = 7.0 Hz, 2H), 2.46 (s, 3H); MS (APCI) m/e 377.1 (M + H)+. 1-(5-(3-Methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (33). Methyl 3-(5-(2-methylpyridin-3yloxy)-6-(3-methylureido)pyridin-3-ylthio)propanoate (400 mg, 1.06 mmol) was dissolved in THF (6 mL) and nitrogen bubbled through for 5 min. Potassium 2-methylpropan-2-olate (3188 μL, 3.19 mmol, 1 M in THF) was added and the mixture stirred vigorously for 30 s. 1Bromo-3-methoxypropane (138 μL, 1.17 mmol) was added and the mixture stirred at room temperature for 30 min. The reaction was quenched with aqueous NH4Cl, extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated. The residue was purified over silica gel (5% MeOH in EtOAc) to afford 1-(5-(3methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-methylurea (330 mg, 0.910 mmol, 85.7% yield). 1H NMR (CDCl3) δ ppm 9.11 (m, 1H), 8.43 (dd, J = 4.1, 1.8 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.25−7.18 (m, 2H), 6.84 (d, J = 2.0 Hz, 1H), 3.41 (t, J = 5.9 Hz, 2H), 3.28 (s, 3H), 3.00 (d, J = 4.9 Hz, 3H), 2.82 (t, J = 7.0 Hz, 2H), 2.47 (s, 3H), 1.78 (m, 2H); MS (APCI) m/e 363.0 (M + H)+.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures and characterization of the remaining compounds 8a−38 along with descriptions of enzymatic, structural biology, ADME and pharmacology experiments, and analysis. This material is available free of charge via the Internet at http://pubs.acs.org. Accession Codes

PDB code: 4RCH

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 303-386-1275. Present Addresses

§ T.D.A.: Lycera Corp., 2800 Plymouth Road, NCRC, Building 26, Ann Arbor, Michigan 48109, United States. ∥ S.A.B.: Knopp Biosciences LLC, 2100 Wharton Street, Suite 615, Pittsburgh, Pennsylvania 15203, United States. ⊥ K.R.C.: Celgene Corporation, 10300 Campus Point Drive, Suite 100, San Diego, California 92121, United States.

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G.; Risley, H.; Bian, J.; Stevens, B. D.; Bourassa, P.; D’Aquila, T.; Baker, L.; Barucci, N.; Robertson, A. S.; Bourbonais, F.; Derksen, D. R.; MacDougall, M.; Cabrera, O.; Chen, J.; Lapworth, A. L.; Landro, J. A.; Zavadoski, W. J.; Atkinson, K.; Haddish-Berhane, N.; Tan, B.; Yao, L.; Kosa, R. E.; Varma, M. V.; Feng, B.; Duignan, D. B.; El-Kattan, A.; Murdande, S.; Liu, S.; Ammirati, M.; Knafels, J.; Dasilva-Jardine, P.; Sweet, L.; Liras, S.; Rolph, T. P. Discovery of (S)-6-(3-cyclopentyl-2(4-(trifluoromethyl)-1H-imidazol-1-yl) propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. J. Med. Chem. 2012, 55, 1318−1333. (d) Wilding, J. P. H.; Leonsson-Zachrisson, M.; Wessman, C.; Johnsson, E. Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin. Diabetes Obes. Metab. 2013, 15, 750−759. (e) Meininger, G. E.; Scott, R.; Alba, M.; Shentu, Y.; Luo, E.; Amin, H.; Davies, M. J.; Kaufman, K. D.; Goldstein, B. J. Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care 2011, 34, 2560−2566. (11) Lu, M.; Li, P.; Bandyopadhyay, G.; Lagakos, W.; DeWolf, W. E., Jr; Alford, T.; Chicarelli, M. J.; Williams, L.; Anderson, D. A.; Baer, B. R.; McVean, M.; Conn, M.; Veniant, M. M.; Coward, P. Characterization of a novel glucokinase activator in rat and mouse models. PLoS One 2014, 9 (2), e88431. (12) Wood, M. R.; Anthony, N. J.; Buck, M. G.; Kuduk, S. D. WO200563690, 2005. (13) Cooke, A. J.; Edwards, A. S.; Andrews, F. E.; Bennett, D. J.; Nimz, O.; Carswell, E. L. WO2009138438, 2009. (14) Itoh, T.; Mase, T. A general palladium-catalyzed coupling of aryl bromides/triflates and thiols. Org. Lett. 2004, 6, 4587−4590. (15) Avalos, M.; Babiano, R.; Barneto, J. L.; Cintas, P.; Clemente, F. R.; Jimenez, J. L.; Palacios, J. C. Conformation of secondary amides. A predictive algorithm that correlates DFT-calculated structures and experimental proton chemical shifts. J. Org. Chem. 2003, 68, 1834− 1842. (16) Kuhn, B.; Mohr, P.; Stahl, M. Intramolecular hydrogen bonding in medicinal chemistry. J. Med. Chem. 2010, 53, 2601−2611. (17) Grimsby, J.; Berthel, S. J.; Sarabu, R. Glucokinase activators for the potential treatment of type 2 diabetes. Curr. Top. Med. Chem. 2008, 8, 1524−1532.

M.M.: Pre-Clinical Research Services, Inc., 1512 Webster Court, Fort Collins, Colorado 80524, United States. ∞ W.C.V.: Alexion Pharma, 352 Knotter Drive, Cheshire, CT 06410, United States. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED ER, extraction ratio (predicted clearance/hepatic blood flow); GK, glucokinase; GKA, glucokinase activator; HSA, human serum albumin; OGTT, oral glucose tolerance test; Vmax, maximum rate of phosphorylation

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REFERENCES

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