- Structure-activity studies of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder
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A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N′-cyanoguanidines furnished N-{2,2-dichloro-1-[N′-(substituted-pyridin-3-yl)-N′-cyanoguanidino] propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.
- Perez-Medrano, Arturo,Brune, Michael E.,Buckner, Steven A.,Coghlan, Michael J.,Fey, Thomas A.,Gopalakrishnan, Murali,Gregg, Robert J.,Kort, Michael E.,Scott, Victoria E.,Sullivan, James P.,Whiteaker, Kristi L.,Carroll, William A.
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p. 6265 - 6273
(2008/04/05)
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- 2,4-Disubstituted thiazolyl derivatives
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This invention concerns the use of a compound of formula (I′) a N-oxide, pharmaceutically acceptable addition salt, quaternary amine and stereochemically isomeric form thereof, wherein Q is optionally substituted C3-6cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl; or Q is a radical of formula wherein X and Y each independently are O, NR3, CH2 or S, with R3 being hydrogen or C1-4alkyl; q is 1 to 4; Z is O or NR4 with R4 being hydrogen or C1-4alkyl; r is 1 to 3; L is optionally substituted phenyl or L is Het with Het being an optionally substituted five- or six-membered heterocyclic ring or an optionally substituted bicyclic heterocyclic ring; for the manufacture of a medicament for the prevention or the treatment of diseases mediated through cytokines.
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- Experimental and Computational Studies of Trifluoromethylation of Aromatic Amines by the System Trifluoroiodomethane-Zinc-Sulfur Dioxide
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Several trifluoromethyl-substituted aromatic and heteroaromatic amines have been obtained by the reactions of the corresponding amines with the title reagent system.Computational results provide rationalization for the observed regioselectivities and support a mechanism in which the electrophilic trifluoromethyl radicals interact with the aromatic ring at the sites with the greatest electron density of the HOMO orbitals, and then the resultant adducts are oxidized to cations.The products obtained are potential building blocks for a number of heterocyclic systems.
- Strekowski, Lucjan,Hojjat, Maryam,Petterson, Steven E.,Kiselyov, Alexander S.
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p. 1413 - 1416
(2007/10/02)
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