The first drugs designed by computers are finally ready for U.S.clinical trials.

One of these, Agouron Pharmaceuticals Inc.'s anti-tumor agent,is already in Phase I human trials in Britain at hospitalsassociated with the University of Newcastle upon Tyne. Theother, BioCryst Pharmaceutical Inc.'s compound for treatinginflammatory autoimmune diseases, should be in clinicals bythe first part of November, said Frederick Dechow, BioCryst'spresident and chief executive officer.

Agouron (NASDAQ:AGPH) of San Diego relies solely onstructure-based drug design for coming up with syntheticdrugs to treat life-threatening diseases. "We're not a biotechcompany per se," Donna Nichols, Agouron's director ofcorporate communications, told BioWorld. And Agouron's anti-tumor agent AG-337 is the "first drug made with protein-baseddrug design to enter clinical trials for cancer," Nichols said.

AG-337 is a small synthetic chemical compound designedspecifically to inactivate the enzyme thymidylate synthase (TS)required for the rapid proliferation of cancer cells. Agouronactually has three drugs that target TS -- AG-85, AG-331 andAG-337 -- in advanced development, Nichols said. Sheexplained that AG-85, which is a topical application forpsoriasis, should be ready for clinical studies in a reformulatedversion this year.

Although the three compounds all target TS, they arestructurally distinct from one another. "The three compoundswork on different parts of the enzyme's active site, and havedifferent pharmacological values," Nichols said.

In structure-based drug design, one of the first tasks is todetermine the crystallographic structure and characterize atthe molecular level an enzyme's active site. Once the active siteis "mapped," "there is essentially no limit to the number ofmolecules that can inhibit an enzyme," explained MichaelVarney, Agouron's director of medicinal chemistry.

But the researchers narrow the choices of synthetic-moleculedrug candidates by a number of criteria that define the"quality" of their fit with the active site. For TS, Varney said,"we probably made as many as 20 different families ofmolecules. ... We reduced these to three clinical candidates."

Privately held BioCryst Pharmaceuticals of Birmingham, Ala.,also uses structure-based drug design to come up with drugs totreat inflammatory autoimmune diseases. Its BCX-34compound is designed to inhibit the enzyme purine nucleosidephosphorylase (PNP), which has been shown to control theproliferation of T cells that occurs during inflammation.BioCryst researchers design their synthetic drug candidates byan iterative procedure that whittles down the list of chemicalstructures that interact with PNP's active site to those thathave pharmacological effects.

"It took us 18 months to come up with 56 compounds and sixfamilies of PNP inhibitors that worked at the nanomolar level,"Dechow told BioWorld. "BCX-34 looks like a good candidate fortreating both psoriasis and cutaneous T-cell lymphoma," hesaid. Because BCX-34 will be given as an ointment, "wespecifically selected it for its dermal properties," Dechowadded.

Initial clinical trials on BCX-34 for both indications should startin early November; "one indication should follow the other by afew days," Dechow predicted.

-- Jennifer Van Brunt Senior Editor

(c) 1997 American Health Consultants. All rights reserved.

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