The objective of this research is to develop new drugs to treat urinary incontinence, an affliction of a growing segment of the population, especially the elderly. There is a need for improved treatment of the most common type, Urge Incontinence, because current drugs have undesirable anticholinergic and arrythmogenic side effects. In phase I we identified a lead compound for further development. The research plan for phase II combines: (1) continued evaluation of the pharmacological properties of the lead compound, the (S)-bis-hydroxyethyl amide analog of oxybutynin (DIHED). Approaches will include: in vitro antispasmodic activity using guinea pig bladder strips and activity in in vivo models as described in section 4. (2). synthesis of additional derivatives with hydroxyalkylamino substitutions and expected longer duration of action. These compounds will have a ketomethyl group or a,a-dimethyl ester group in place of the labile ester of oxybutynin. (3). continued testing of all new compounds, including studies of binding to calcium channels and muscarinic receptors, in vitro activity using guinea pig bladder strips, and activity in in vivo models as described in section 4. (4). optimization of synthetic and chiral resolution methods and scale-up production to afford the quantities of drug candidates needed for the studies. Commercial laboratories for GMP syntheses will ultimately be identified for the lead clinical candidate. (3). identification of one or more lead drug candidates to carry forward, in collaboration with Bridge Pharma Inc. and possibly with Merck and Co., McNeil Consumer Healthcare or another """"""""big pharma"""""""", with preclinical studies to support an Investigational New Drug (IND) application to the FDA. Health relatedness. The demand for improved medication of Urge Incontinence is very strong. This work will result in the development of new drugs to treat the disease with no side effects, and is both technologically innovative and highly relevant to human health.
New drugs for Urge Incontinence have a potential market of approximately one billion dollars in the United States. The compounds which we will synthesize and develop will have high efficacy and low toxicity. Drugs emerging from this work should have excellent potential for commercial development.
