GSK-1292263
1032823-75-8
3-isopropyl-5-(4-(((6-(4-(methylsulfonyl)phenyl)pyridin-3-yl)oxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole
5-[1-(3-Isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ylmethoxy]-2-[4-(methylsulfonyl)phenyl]pyridine
C23H28N4O4S
Mass: 456.18313
1292263
GSK-1292263
GSK-1292263A
GSK-263A
GSK-1292263 is a novel GPR119 receptor agonist that is currently under development for the treatment of type 2 diabetes. Treatment of male Sprague-Dawley rats with a single dose of GSK-1292263 (3-30 mg/kg) in the absence of nutrients correlated with increased levels of circulating gastrointestinal peptides; glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY) and glucagon.
GSK-1292263 had been evaluated in phase II clinical studies at GlaxoSmithKline for the oral treatment of type 2 diabetes and as monotherapy or in combination with sitagliptin for the treatment of dyslipidemia; however no recent development has been reported for this research.
Following administration of glucose in the oral glucose tolerance test (OGTT), greater increases in total GLP-1, GIP and PYY were seen in GSK-1292263-treated rats than in control animals. Despite significant decreases in the glucose AUC, no statistically significant differences in insulin responses and insulin AUC were observed between rats administered GSK-1292263 and those receiving vehicle control.
In the intravenous glucose tolerance test, significant increases in the peak insulin response and insulin AUC(0-15 min) of 30-60% were reported in the GSK-1292263 treatment group, compared with values in the vehicle control cohort. This insulin upregulation correlated with a significant increase in the glucose disposal rate (Brown, K.K. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 407).
The safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of GSK-1292263 were evaluated in a recently completed randomized, placebo-controlled clinical trial in healthy volunteers (ClinicalTrials.gov Identifier NCT00783549).
A total of 69 subjects received single escalating doses of GSK-1292263 (10-400 mg) prior to administration of a 250-mg dose given once daily for 2 and 5 days, which was also evaluated in combination with sitagliptin (100 mg). Treatment with GSK-1292263 at all doses was described as well tolerated, with the most common drug-related effects being mild headache, dizziness, hyperhidrosis, flushing and post-OGTT hypoglycemia.
Hypoglycemia was not reported with the 5-day dosing schedule. Pharmacokinetic profiling revealed dose-proportional AUC and Cmax at single lower doses, but not at single higher ones. Following repeated once-daily dosing (5 days), drug accumulation was observed consistent with a mean half-life of 12-18 hours. A dose-dependent increase in glucose AUC(0-3 h) during OGTT was seen in GSK-1292263-treated subjects. The treatment was also associated with an increase in PYY during the prandial periods.
Coadministration with sitagliptin led to increases in the plasma concentrations of active GLP-1 but reduced the levels of total GLP-1, GIP and PYY. Sitagliptin affected the exposure to GSK-1292263 (50% increase) but GSK-1292263 did not affect sitagliptin exposure. The data support further evaluation of GSK-1292263 for the treatment of type 2 diabetes (Source: Nunez, D.J. et al. Diabetes [70th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 25-29, Orlando) 2010] 2010, 59(Suppl. 1): Abst 80-OR).
WO 2008070692
http://www.google.com.au/patents/WO2008070692A2?cl=en
Example 169: 5-[({1 -[3-(1 -Methylethyl)-1,2,4-oxadiazol-5-yl]-4- piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine hydrochloride
Step 1 : A mixture of 6-bromo-3-pyridinol (7 g, 40 mmol), [4-(methylsulfonyl)phenyl]boronic acid (8 g, 40 mmol), 2M Na2CO3 (30 ml_), PdCI2(PPh3)2 (1 g) and DME (60 ml.) under N2 was heated at 80 0C overnight. The reaction was allowed to cool to room temperature and was diluted with EtOAc and water. The resulting precipitate was filtered off and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The aqueous phase was also concentrated. Each of the residues was recrystallized from MeOH. The solid material from the organic phase recrystallization and the mother liquors from both aqueous and organic recrystallizations were combined, concentrated and purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2CI2 to give 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (2.9 g, 29%) as a tan solid. Step 2: Diisopropyl azodicarboxylate (0.175 ml_, 0.89 mmol) was added dropwise to a solution of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (150 mg, 0.59 mmol), {1-[3-(1- methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 200 mg, 0.89 mmol), PPh3 (233 mg, 0.89 mmol), and THF (10 ml.) at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was concentrated, and the resulting crude was purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (10:90 to 100:0) with 0.05% TFA as a modifier, then taken up in CH2CI2 and free-based with saturated NaHCO3 (aq) to give 5-[({1-[3-(1-methylethyl)-1 ,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4- (methylsulfonyl)phenyl]pyridine (220 mg) as a white solid. Step 3: A mixture of the resulting white solid (50 mg, 0.1 1 mmol) in THF (3 ml.) was stirred at ambient temperature as 4Λ/ HCI in dioxane (28 μl_) was added dropwise. The resulting white precipitate was filtered, air-dried, then triturated with diethyl ether to give 35 mg (65%) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3): δ 8.46 (d, 1 H, J = 0.7 Hz), 8.18 (bs, 2H), 8.05 (bs, 2H), 7.83 (bs, 1 H), 7.61- 7.45 (m, 1 H), 4.24 (d, 2H, J = 10.4 Hz), 4.00 (d, 2H, J = 0.6 Hz), 3.21-3.03 (m, 5H), 2.89 (m, 1 H), 2.15 (d, 1 H, J = 1.1 Hz), 1.96 (bs, 2H), 1.50 (bs, 2H), 1.28 (d, 6H, J = 6.9 Hz); LRMS (ESI), m/z 457 (M+H).
Filed under: Phase2 drugs Tagged: GSK-1292263
