NOVEL DRUG FOR URINARY INCONTINENCE

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The most common type of urinary incontinence, Urge Incontinence, is inadequately treated, largely because current drugs have undesirable anticholinergic side effects that are especially problematic among the elderly. It has recently been suggested that the bladder instability underlying this disorder is mediated by calcium channels rather than cholinergic receptors. The current drug of choice for Urge Incontinence, racemic oxybutynin, has both potent calcium channel antagonistic and anticholinergic activities, but it has membrane stabilizing effects that could cause cardiodepression. The specific aims of phase I of this program, therefore are: 1. To synthesize a series of specifically designed derivatives of oxybutynin, both as racemates and as the S-enantiomers; 2. To obtain a pharmacological profile of the compounds that will be predictive of efficacy in treating Urge Incontinence, i.e. binding to diltiazem and verapamil binding sites on calcium channels; 3.To obtain a pharmacological profile of the compounds that will be predictive of side effects, i.e. binding to muscarinic receptors and cardiodepressant activity in vitro; 4.Based on the results of aims 1-3, to synthesize isosteric derivatives of promising compounds that will have prolonged duration of in vivo. In cooperation with Bridge Pharma Inc. one or more compounds emerging from the phase I program will undergo additional testing of its (their) pharmacological and toxicological properties, with the goal of filing and Investigational New Drug application with the Food and Drug Administration at the end of phase II. PROPOSED COMMERCIAL APPLICATION New drugs for Urge Incontinence have a potential market of approximately one billion dollars in the United States. The compounds which we will synthesize have high efficacy and low toxicity. Drugs emerging from this work should have excellent potential for commercial development.