- COMPOUNDS AND COMPOSITIONS FOR USE IN AUGMENTATION OF GLUCOSE UPTAKE AND INSULIN SECRETION
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The present invention is directed to compounds such as: formula wherein linker is independently selected from the group consisting of -S-, -S-S-, -S-(CH2)n-, -NH-, -NH-(CH2)n-, -0-, -S02-, arylene, heteroarylene; Rl is selected from the group consisting of straight or branched C4- C20 alkyl, straight or branched C4-C20 alkenyl, straight or branched C4-C20 alkynyl, each optionally interrupted with at least one NH, C5- C7 saturated cycloalkyl or heteroalkyl ring, C5-C12 aromatic or het- eroaromatic ring, each optionally substituted with at least one group selected from -COOH, -NH2, C1-C8 alkoxy, C1-C5 amidyle, C1-C5 car- boxyl, halogen; and R2 is independently selected from the group consisting of H, OH, SH, NH2, N02, halogen, CN, C1-C8 alkoxy, C1-C5 carboxylic acid, straight or branched C1-C8 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2 - C12 alkynyl each optionally substituted by at least one substituent selected from the group consisting of C1-C5 alkoxy, C1-C5 carboxylic acid, OH, SH, NH2, halogen; and compositions for use in the treatment of diabetes and related dis? orders.
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- Synthesis and mechanism of hypoglycemic activity of benzothiazole derivatives
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Adenosine 5′-monophosphate activated protein kinase (AMPK) has emerged as a major potential target for novel antidiabetic drugs. We studied the structure of 2-chloro-5-((Z)-((E)-5-((5-(4,5-dimethyl-2-nitrophenyl)furan-2-yl) methylene)-4-oxothiazolidin-2-ylidene)amino)benzoic acid (PT-1), which attenuates the autoinhibition of the enzyme AMPK, for the design and synthesis of different benzothiazoles with potential antidiabetic activity. We synthesized several structurally related benzothiazole derivatives that increased the rate of glucose uptake in L6 myotubes in an AMPK-dependent manner. One compound, 2-(benzo[d]thiazol-2-ylmethylthio)-6-ethoxybenzo[d]thiazole (34), augmented the rate of glucose uptake up to 2.5-fold compared with vehicle-treated cells and up to 1.1-fold compared to PT-1. Concomitantly, it elevated the abundance of GLUT4 in the plasma membrane of the myotubes and activated AMPK. Subcutaneous administration of 34 to hyperglycemic Kuo Kondo rats carrying the Ay-yellow obese gene (KKAy) mice lowered blood glucose levels toward the normoglycemic range. In accord with its activity, compound 34 showed a high fit value to a pharmacophore model derived from the PT-1.
- Meltzer-Mats, Ella,Babai-Shani, Gali,Pasternak, Lily,Uritsky, Neta,Getter, Tamar,Viskind, Olga,Eckel, Jürgen,Cerasi, Erol,Senderowitz, Hanoch,Sasson, Shlomo,Gruzman, Arie
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p. 5335 - 5350
(2013/07/26)
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- Topically active ocular benzothiazole sulfonamide carbonic anhydrase inhibitors
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This invention is directed to compounds of the formula STR1 and pharmaceutically acceptable salts thereof wherein R6 is hydrogen or lower alkyl; each R1 is hydrogen, lower alkyl, halogen, nitro, trihaloalkyl, lower alkoxy, formyl, lower alkanoyl, loweralkylamino or diloweralkylamino STR2 X is O, S or NR5 ; R2 is OR7 or NR7 R8 ; each R3 and R4 are independently hydrogen or lower alkyl; R5 R7 and R8 are independently hydrogen or lower alkyl; n is 0-3 and m is 0-6. These compounds are useful for treating glaucoma or assessing corneal function in mammals.
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- Topically Active Carbonic Anhydrase Inhibitors. 1. O-Acyl Derivatives of 6-Hydroxybenzothiazole-2-sulfonamide
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A series of O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide (4, L-643,799) was prepared and the potential utility of each series member as a topically active inhibitor of ocular carbonic anhydrase was determined.In vitro studies showed these esters to be substrates for ocular esterases which liberate 4 during corneal translocation.The most interesting series member, 2-sulfamoyl-6-benzothiazolyl 2,2-dimethylpropionate (22, L-645,151), acting as a prodrug form of 4, was found to enhance delivery through the isolated albino rabbit cornea by 40-fold when compared to the parent phenol 4.Studies in rabbits revealed that 22 is a potent topically active ocular hypotensive carbonic anhydrase inhibitor.
- Woltersdorf, O. W.,Schwam, H.,Bicking, J. B.,Brown, S. L.,deSolms, S. J.,et al.
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p. 2486 - 2492
(2007/10/02)
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- Gastric cytoprotection with heterocyclic sulfonamides
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The present invention provides a method for gastrointestinal cytoprotection using a class of heterocyclic sulfonamides.
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