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(12) Patent Application Publication (10) Pub. No.: US 2014/0221286 A1 Belardinelli Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0221286 A1 Belardinelli Et Al US 20140221286A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0221286 A1 Belardinelli et al. (43) Pub. Date: Aug. 7, 2014 (54) SODIUM CHANNEL BLOCKERS REDUCE A613 L/4453 (2006.01) GLUCAGON SECRETION A63/545 (2006.01) A6II 45/06 (2006.01) (71) Applicant: Gilead Sciences, Inc., Foster City, CA A63/64 (2006.01) (US) A613 L/405 (2006.01) A613 L/45 (2006.01) (72) Inventors: Luiz Belardinelli, Palo Alto, CA (US); A63L/92 (2006.01) Arvinder Dhalla, Mountain View, CA A613 L/4439 (2006.01) (US) A63/67 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/345,893 CPC ............... A61K 38/28 (2013.01); A61 K3I/I67 1-1. (2013.01); A61 K3I/138 (2013.01); A61 K (22) PCT Filed: Sep. 20, 2012 3 1/4458 (2013.01); A61 K3I/4965 (2013.01); 86) PCT No.: PCT/US2O12/056419 A6 IK3I/519 (2013.01);s A61 K3I/341 (86) O (2013.01); A61 K3I/49 (2013.01); A61 K S371 (c)(1), 3 1/166 (2013.01); A61 K3I/4402 (2013.01): (2), (4) Date: Mar. 19, 2014 A61K 31/4166 (2013.01); A61 K3I/4453 (2013.01); A61 K3I/5415 (2013.01); A61 K Related U.S. Application Data 45/06 (2013.01); A61 K3I/64 (2013.01); A61 K (60) Provisional application No. 61/537,411, filed on Sep. 31/4015 (2013.01); A61K 31/451 (2013.01): 21, 2011 A6 IK31/192 (2013.01); A61 K3I/4439 s (2013.01) Publication Classification USPC ............ 514/6.5: 514/626; 514/651; 514/331; 514/255.06; 514/249; 514/471; 514/305; (51) Int. Cl. 514/619; 514/357: 514/391; 514/225.2: A6 IK38/28 (2006.01) 514/592: 514/423: 514/563; 514/342:564/194; A6 IK3I/38 (2006.01) 564/354; 546/233; 546/333; 544/407: 544/260: A6 IK3I/4458 (2006.01) 548/321.1; 435/375 A6 IK3I/4965 (2006.01) A 6LX3/59 (2006.01) (57) ABSTRACT A6 IK3I/34 (2006.01) It is discovered that sodium-channel blockers inhibit the A6 IK3I/49 (2006.01) secretion of glucagon from pancreatic alpha cells. The A6 IK3I/66 (2006.01) present disclosure, based on Such discoveries, provides com A6 IK3I/4402 (2006.01) positions and methods for the treatment of hyperglycemia and A6 IK3I/4I66 (2006.01) related diseases and conditions with Na-channel blockers. Patent Application Publication Aug. 7, 2014 Sheet 1 of 16 US 2014/0221286 A1 A (N=4-5) 100 7 5 255O O SS ° N S S V Ranolazine (uM) B C 9 100 5 E 75 23 36 50 S SSS 25 V Compound A (uM) C 100 7 5 5 O 2 5 Patent Application Publication Aug. 7, 2014 Sheet 2 of 16 US 2014/0221286 A1 A (N=9) C 100 2 CD5S 75 23So 50 36 geNS 25 CD O s V Ranolazine (uM) B 100 7 5 25 5O Compound A (uM) FG. 2 Patent Application Publication Aug. 7, 2014 Sheet 3 of 16 US 2014/0221286 A1 A 500 9 -o 400 of& d 300 O g's 200 s 100 CD O e e N b NS rS S. S y a\ Ranolazine (uM) Veratridine (30 uM) B 400 9. 300 85 5 200 b 8 & 100 B CD O aV(2) aS(2. Compound A (uM) Veratridine (30 uM) Ne N S S is TTX (nM) Veratridine (30 uM) FIG. 3 Patent Application Publication Aug. 7, 2014 Sheet 4 of 16 US 2014/0221286 A1 A C O s 1200 E 900 CD O U 600 38 s 300 0. & V V Ranolazine (uM) Veratridine (30 uM) Compound A (uM) Veratridine (30 uM) FIG. 4 Patent Application Publication Aug. 7, 2014 Sheet 5 of 16 US 2014/0221286 A1 A S.C 800 d 2. 600 5 CS 400 85 O ses 200 s O s O N NQ s'Q SSy y V TTX (nM) Veratridine (15 uM) B 24. OO OO Compound A (uM) Veratridine (15 uM) FIG.S Patent Application Publication Aug. 7, 2014 Sheet 6 of 16 US 2014/0221286 A1 A (N=3-4) 1000 as 2. 750 (f)2 3 500 88 8& 250 CD O a\ Epinephrine (uM) 4 O O 213 OOO OOO Ranolazine (uM) Epinephrine (5 uM) F.G. 6 Patent Application Publication Aug. 7, 2014 Sheet 7 of 16 US 2014/0221286 A1 & N S S S L-Arginine (mM) 1200 800 20 mM L-Arginine FIG. 7 Patent Application Publication Aug. 7, 2014 Sheet 8 of 16 US 2014/0221286 A1 Cotro FG. 8 Patent Application Publication Aug. 7, 2014 Sheet 9 of 16 US 2014/0221286 A1 FIG. 9 Patent Application Publication Aug. 7, 2014 Sheet 10 of 16 US 2014/0221286 A1 A s E400o CD 3300 CD E. (P 200 As E ( 100 al o S O As B B 4-Week 8-Week FIG 10 Patent Application Publication Aug. 7, 2014 Sheet 11 of 16 US 2014/0221286 A1 A Nofa S2 Weicise S2 + Raciazine Patent Application Publication Aug. 7, 2014 Sheet 12 of 16 US 2014/0221286 A1 A B I Wehicle a w8 Ranolazine S. 500 10 - Compound A E & Sitagliptin o 400 - d & 8 300 c 5 6 s 200 100 4 2 O 2 4. 8 10 LL. 0 2 O 2 4 6 8 10 C Weeks of treatment D Weeks of treatment 60O 1 2 5 1 OO 75 25 O 2 4 O 2 4 6 8 10 Patent Application Publication Aug. 7, 2014 Sheet 13 of 16 US 2014/0221286 A1 Wehicle Ranolazine Compound A Sitagliptin FIG. 13 Patent Application Publication Aug. 7, 2014 Sheet 14 of 16 US 2014/0221286 A1 Ran Compa A Sitagliptin D Vehicle : Ranolazine Compound A Sitagliptin 00(_) Ran Compd A Sitagliptin F.G. 14 Patent Application Publication Aug. 7, 2014 Sheet 15 of 16 US 2014/0221286 A1 Rat Islets (N=3-6) 0.008 0.006 0.004 0.002 0.000 FIG. 15 Patent Application Publication Aug. 7, 2014 Sheet 16 of 16 US 2014/0221286 A1 A C O O CD CD O O) v 9 B CD as C O 0 s O 20 40 60 80 100 % inhibition of Nay 1.3 B 100 80 60 40 20 O 20 40 60 80 100 % inhibition of Nay 1.7 FG 16 US 2014/0221286 A1 Aug. 7, 2014 SODIUM CHANNEL BLOCKERS REDUCE uptake of glycosylated proteins by macrophages stimulates GLUCAGON SECRETION the secretion of pro-inflammatory cytokines by these cells. The cytokines activate or induce degradative and proliferative CROSS REFERENCE TO RELATED cascades in mesenchymal and endothelial cells respectively. APPLICATIONS 0009. The glycation of hemoglobin provides a convenient method to determine an integrated and long-term index of the 0001. This application claims the benefit under 35 U.S.C. glycemic state. The level of glycosylated proteins reflects the S119(e) of U.S. Provisional Application Ser. No. 61/537,411 level of glucose over a period of time and is the basis of an filed Sep. 21, 2011, the content of which is incorporated by assay referred to as the hemoglobin A1c (Hb A1c) assay. reference in its entirety into the present disclosure. 0010 Thus, controlling blood glucose levels is a desirable FIELD therapeutic goal. A number of oral antihyperglycemic agents are known. Medications that increase the insulin output by the 0002 Methods are provided for treating diabetes, lower pancreas include Sulfonylureas (including chlorpropamide ing plasma levels of glucose and Hb Alc and delaying onset of (Orinase(R), tolbutamide (Tolinase(R), glyburide (Micron diabetic complications in a diabetic or pre-diabetic patient. ase?R), glipizide (Glucotrol(R), and glimepiride (Amaryl(R)) and meglitinides (including reparglinide (Prandin R) and BACKGROUND nateglinide (Starlix(R)). Medications that decrease the 0003 Diabetes mellitus is a disease characterized by amount of glucose produced by the liver include biguanides hyperglycemia; altered metabolism of lipids, carbohydrates (including metformin (Glucophage(R). Medications that and proteins; and an increased risk of complications from increase the sensitivity of cells to insulin include thazo vascular disease. Diabetes is an increasing public health prob lidinediones (including troglitaZone (Resulin(R), pioglita lem, as it is associated with both increasing age and obesity. Zone (Actos(R) and rosiglitazone (Avandia(R)). Medications 0004. There are two major types of diabetes mellitus: 1) that decrease the absorption of carbohydrates from the intes Type I, also known as insulin dependent diabetes (T1DM), tine include alpha glucosidase inhibitors (including acarbose and 2) Type II, also known as insulin independent or non (Precose(R) and miglitol (Glyset(R)). Actos(R) and Avandia(R) insulindependent diabetes (T2DM or NIDDM). T1DM is due can change the cholesterol patterns in diabetics. PrecoseR) to insufficient amounts of circulating insulin whereas type 2 works on the intestine; its effects are additive to diabetic diabetes is due to a decrease in the response of peripheral medications that work at other sites, such as Sulfonylureas. tissue to insulin. Ultimately, insulin deficiency is present in ACE inhibitors can be used to control high blood pressure, both types of diabetes. treat heart failure, and prevent kidney damage in people with 0005 T1DM results from the body’s failure to produce hypertension or diabetes. ACE inhibitors or combination insulin, the hormone that “unlocks” the cells of the body, products of an ACE inhibitor and a diuretic, such as hydro allowing glucose to enter and fuel them. The complications of chlorothazide, are marketed. However, a need still remains TIDM include heart disease and stroke; retinopathy (eye dis for more effective, safer treatments.
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