Stability studies and structural characterization of caspase inhibitors in aqueous media and in the presence or absence of dithiothreitol

ANYL 147

Vasilios Marathias, marathv@wyeth.com1, Mei-Yi Zhang1, Paul J Dollings, dollinp@wyeth.com2, Wayne E. Childers Jr., childew@wyeth.com1, Lisa M. Havran, havranl@wyeth.com1, Chae-Koo Dan Chong, chongc@wyeth.com1, and Andrew Wood3. (1) Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, (2) Chemical and Screening Sciences, Wyeth Research, Princeton, CN 8000, Princeton, NJ 08543, (3) Neuroscience, Wyeth Research, Princeton, CN 8000, Princeton, NJ 08543
Stability studies have been conducted in aqueous media on a series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidolones) compounds that have been identified as Caspase inhibitors. By using NMR and MS time course methods, the structures and mechanism of conversion have been elucidated. These studies have led to the design of a new series of Caspase inhibitors, which retain both their potency and are substantially more stable in aqueous media. Additionally, a reversible redox reaction was observed with the pyrimidolone series in the presence of Dithiothreitol (DTT), a widely used reducing agent in enzymatic media. The structures and mechanism of the DTT induced reduction/oxidation have also been elucidated.

 

General Papers
7:00 PM-9:00 PM, Sunday, 28 August 2005 Washington DC Convention Center -- Hall A, Poster

Division of Analytical Chemistry

The 230th ACS National Meeting, in Washington, DC, Aug 28-Sept 1, 2005