Non-Sedating Atropisomeric Drugs for Atopic Diseases

DESCRIPTION (provided by applicant): In our program to develop non-sedating ketotifen analogs, we found that norketotifen (NORK) and N-hydroxyethyl-norketotifen (HENK) had significant antiasthmatic and anti-inflammatory activity but less sedation and antimuscarinic activity than ketotifen. These compounds are chiral as a result of atropisomerism. We, therefore, prepared the individual atropisomers, and showed that S-NORK and S-HENK had greater therapeutic activity than the racemates, and that the R-atropisomers had greater sedative and antimuscarinic side effects. In phase I we evaluated the preparation methods, and chemical and metabolic stability of atropisomers of the candidate compounds in order to decide if further development of this class of isomers was warranted. In addition, we have compared the biological stability and began to study pharmacokinetic properties of the atropisomers for the same purpose. We conclude that the atropisomers of NORK and HENK are stable in the solid state, less stable in aqueous solution, but in a temperature-dependent manner, and chirally stable in biological milieus. For phase II we have chosen as "ultimate lead compound" the S-isomer of norketotifen ("SNORK"), and S-hydroxyethyl-norketotifen (SHENK) as a backup compound. The specific aims for this phase II project are: 1. To improve synthetic methods to manufacture SNORK in high chemical yield and in high enantiomeric excess. 2. To develop and validate analytical methods suitable for analysis of intermediates and drug substance. 3. To perform metabolism studies of SNORK in vitro, using human microsomes and hepatocytes, and in vivo, in relevant animals. 4. To prepare ca. one kilogram of GMP-grade SNORK for first in man studies. 5. To perform additional pharmacological studies and safety pharmacological studies, using methodology described in this application. 6. To perform toxicological studies necessary for regulatory approval of an IND. 7. To write an IND application for SNORK, to conduct a pre-IND meeting with the FDA, and to file the IND with the FDA. The aim is to license this project to a company with experience in drug development and regulatory approval, and the ability to commercialize the drug in the U.S. and worldwide. Successful conclusion of this work will afford the first example of an atropisomeric drug approved for clinical trials by the FDA.