Abstract
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.
MeSH terms
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Administration, Oral
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Animals
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Benzamides / chemical synthesis*
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Benzamides / pharmacokinetics
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Benzamides / pharmacology
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Biological Availability
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Crystallography, X-Ray
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Dogs
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Electric Stimulation
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Female
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Guanidines / chemical synthesis*
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Guanidines / pharmacokinetics
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Guanidines / pharmacology
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Humans
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In Vitro Techniques
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Ion Channel Gating
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KATP Channels / agonists
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KATP Channels / physiology*
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Muscle Relaxation
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Potassium Channels, Inwardly Rectifying / agonists
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Potassium Channels, Inwardly Rectifying / physiology
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Structure-Activity Relationship
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Swine
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Urinary Bladder / cytology
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Urinary Bladder / drug effects
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Urinary Bladder / physiology
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Urinary Bladder, Overactive / drug therapy*
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Urinary Bladder, Overactive / physiopathology
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Urodynamics
Substances
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4-chloro-N-(2,2-dichloro-1-(N'-(6-chloropyridin-3-yl)-N''-cyanoguanidino)propyl)benzamide
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Benzamides
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Guanidines
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KATP Channels
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Kir6.2 channel
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Potassium Channels, Inwardly Rectifying