Novel aldehyde dehydrogenase-2 inhibitors as a potential treatment of alcohol addiction

MEDI 253

Jeff Zablocki1, Matthew Abelman1, Michael G. Organ, organ@yorku.ca2, Yaroslav Bilokin2, Guan Cao2, Debasis Malik2, Wing Ming Keung3, Guoxin Tao3, David Overstreet4, Daniel Soohoo5, Nancy Chu5, Jia Hao5, Kwan Leung5, Hugh Genin6, Maria Pia Arolfo7, Lina Yao7, Peidong Fan7, and Ivan Diamond7. (1) Department of Bioorganic Chemistry, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA 94304, (2) Department of Chemistry, Toronto Total Synthesis, 291 Northshore Boulevard West, Burlington, ON L7T1A6, Canada, (3) Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, (4) Department of Psychiatry, University of North Carolina at Chapel Hill, 3009 Thurston Bldg, Chapel Hill, NC 27599, (5) Department of Pre-Clinical Development, CV Therapeutics, Inc, (6) Accelrys Inc, 9685 Scranton Road, San Diego, CA 92121, (7) Department of Neuroscience, CV Therapeutics, Inc
Daidzin 1, inhibits aldehyde Dehydrogenase-2 (ALDH-2, IC50 = 40 nM) and is the active principle of an ancient Chinese herbal medicine “kudzu root” that has been used to treat alcohol addiction for over a 1000 years. Although “kudzu root” has some effect in humans, the low oral bioavailability and short half-life of the principle daidzin (F < 1% and t1/2 = 0.18 h, rat) has led us to optimize its pharmaceutical properties. In particular, we found replacements for the polar glucose group that led to two distinct series of molecules illustrated by the meta-benzyl acid derivative 2 and the 5-phenyloxadiazolyl compound 3 that retained similar inhibition of the ALDH-2 enzyme and resulted in an increased oral bioavailability and half-life. Both 2 and 3 inhibit alcohol consumption in rodent models in a dose-dependent manner at doses well below those for acamprosate and comparable to those for naltrexone, approved agents for alcohol addiction. The docking poses for 2 and 3 will be presented based on an X-ray of daidzin-ALDH-2 complex.

 

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1:30 PM-4:00 PM, Wednesday, August 22, 2007 BCEC -- 210 B/C, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007