A significant percentage of adults in the US suffer from overactive bladder (OAB), and the problem is more acute in the elderly. Aside from the use of diapers, two drugs currently dominate the market, tolterodine and oxybutynin, but their therapeutic effects are due to their potent antimuscarinic activities. These drugs address only the """"""""atropine-sensitive"""""""" patient population, and are marginally effective because therapeutic doses are limited by severe antimuscarinic side effects, such as dry mouth, blurred vision and memory impairment which are particularly problematic in the elderly. The """"""""uro-selective"""""""" calcium antagonists that we have discovered through this phase II SBIR grant, exemplified by """"""""TBDT"""""""", the 5-t-butyl analog of des-isopropyl tolterodine, inhibit unwanted smooth muscle contractions of the bladder regardless of the reason for the contractions. We, therefore, expect that TBDT will have therapeutic value for all patients suffering from OAB - regardless if they are atropine-resistant or atropine-sensitive. Contrary to other calcium antagonists such as nifedipine and diltiazem, TBDT inhibits bladder contraction but affects neither heart functions nor blood pressure. In contrast with the current therapy, TBDT is not expected to have any antimuscarinic side effects. For this competing renewal application, we propose to improve the synthetic process and analytical methods for TBDT, and carry out the safety pharmacology, toxicology and toxicokinetic studies that will enable us to obtain regulatory (FDA) approval to conduct human clinical trials of TBDT. We have selected the 5-propyl derivative PrBDT as a backup compound.
The specific aims for this project are : 1. To develop synthetic methods to manufacture TBDT, and to prepare salt forms for comparison of stability and oral bioavailability; 2. To use analytical methods for TBDT and its intermediates to support synthesis methods development, and to transfer methods for TBDT analysis for later toxicokinetic studies; 3. To perform metabolism studies of TBDT in vitro, using human microsomes and hepatocytes, and in vivo, in relevant animal species to be used for toxicology; 4. To perform safety pharmacological studies, using methodology described in this application; 5. To perform toxicological studies necessary for regulatory approval of an IND; 6. To write the IND application for TBDT and to conduct a pre-IND meeting with the FDA. The ultimate aims are to license this project to a company with experience in drug development and regulatory approval, and the ability to commercialize the drug in the United States and worldwide. Our partner Bridge Pharma Inc. has previous experience in outlicensing research projects. Successful conclusion of the present work will generate the data necessary to license the drug or to initiate human clinical trials. A drug for OAB acting by a novel mechanism will not only be competitive commercially, but will improve compliance and quality of life of the elderly. Increasing incidence of overactive bladder (OAB) in the elderly creates a major challenge for treatment of this affliction. The alternatives today are diapers or drugs, such as terodiline and oxybutynin, which have significant anticholinergic side effects especially in older patients. The new drug class under development by GLSynthesis and Bridge Pharma, uro-selective calcium antagonists, promise to have high therapeutic benefit without the typical side effects of the current drugs. The new drug will greatly increase the quality of life of persons with OAB. ? ? ?
