Alfred Burger Award in Medicinal Chemistry

Sponsored by GlaxoSmithKline

Joel R. Huff's determination and creativity in bringing the chemistry of protease inhibitors to market is a major victory in the war on AIDS.

The award-winning work was done while Huff was at Merck Research Laboratory in West Point, Pa., where he led the development of the HIV protease inhibitor indinavir (Crixivan), the most successful of the early protease inhibitors. "In my 25 years as a consultant to the pharmaceutical industry, the Crixivan drug development efforts stand as the greatest achievement I have witnessed," says David A. Evans, the Abbott & James Lawrence Professor of Chemistry at Harvard.

Huff's work was critical to the development of this important drug. He identified the problems in trying to develop a very hydrophobic lead compound into an effective drug. He predicted that increasing the polarity and reducing the molecular weight of the compound would make the drug effective by decreasing both the oxidative metabolism of the compound and its protein binding. "His insights were critical," according to Samuel J. Danishefsky, professor of chemistry at Columbia University, "not only at the level of issues of activity and feasibility of synthesis but in the even more complicated issues of pharmacokinetics."

The search for a protease inhibitor also led Huff to discover a candidate compound for another HIV weapon, a nonnucleoside reverse transcriptase inhibitor. His perseverance in overcoming the pharmacokinetic barriers to development of this drug, efavirenz (Sustiva), resulted in a second major drug for AIDS sufferers. Huff says he is especially pleased with this drug because of its continuing importance in AIDS treatment. "The discovery of an effective reverse transcriptase inhibitor was a major challenge with numerous pitfalls," Evans notes. "Huff provided the leadership that delivered" the results.

Huff has had success outside of HIV research. Other contributions include the total synthesis of d- and l-myo-inositol-1,4,5-triphosphate, a mediator for regulation of intracellular calcium ion concentration. The practical synthesis of these enantiomers replaces tedious isolation of the compounds from natural sources. Huff also worked on the design and synthesis of a highly selective and orally bioavailable inhibitor of p38 mitogen-activated protein kinase, which may be used to treat the underlying causes of inflammation.

After getting his B.S. in chemistry at the University of Texas, Austin, Huff went to Massachusetts Institute of Technology, where he received a Ph.D. in organic chemistry in 1974. Although he had intended to pursue an academic career, Huff says medicinal chemistry provided him an opportunity to do something with a real impact. "I saw the chance to do something with the potential to affect the lives of other people, to do something really important," he says. Huff, 59, worked in the medicinal chemistry department at Merck for 30 years before retiring in 2004 and is now a private consultant.

Huff received the Directors Award from Merck's board of directors in 1998. He was a recipient of the Discoverers Award from the Pharmaceutical Research & Manufacturers of America in 1999 and was awarded the ACS Philadelphia Section Award in 2002.

The award address will be presented before the Division of Medicinal Chemistry.-David Hanson