NEWS OF THE WEEK
AIDS DRUG FROM MERCK Attaining low-cost production may be vital f a promising new drug to treat AIDS should prove out, the developer— Merck Co. of Rahway, N.J.—could be faced with manufacturing the first drug ever for which the cost of production is a crucial factor in commercialization. How that situation affects Merck and how the firm intends to deal with it were outlined in talks at Chiral USA '94, a conference and exposition on issues in enantiomeric compounds just held in Reston, Va. Paul J. Reider, Merck's executive di rector of process research, points out that company chemists have devised a lowcost, high-yield process to produce the drug, an inhibitor of a key enzyme in human immunodeficiency virus (HIV). The drug is now being tested in large numbers of patients with AIDS (Phase Π-ΙΠ clinical trials), Reider says. Having a dependable, high-yield pro cess is essential to prevent interruption of drug supplies. Drug shortages could cause relapses in AIDS patients and emergence of drug-resistant HIV strains. But the importance of low-cost produc tion was underscored in a talk at the Reston conference by Paul van Eikeren, vice president for research and development at Sepracor, Marlborough, Mass. Merck turned to Sepracor to develop part of the process to make the new drug. Van Eikeren notes that for AIDS drugs of the Merck type, patients must take up to 3 g per day, amounting to about 1 kg per person per year. He quotes estimates of 250,000 reported AIDS cases in North America and more than 1 million HIV infections there. Worldwide, the numbers are 600,000 and 13 million. Thus, if the drug should make it through the approv al process—which could take years—and if it were used to treat all HIV infections, production needs could be on the order of thousands of metric tons per year. By contrast, van Eikeren points out, production of a best-selling "block buster" prescription drug can range from 50 to 150 metric tons per year. At such production levels, the cost of syn-
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MAY 16,1994 C&EN
Aminoindanol group is key component of AIDS drug...
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thesizing a drug is a relatively insignif icant consideration. However, production of Merck's AIDS drug could reach commodity-chemical scale, where production costs can be par amount. Yet the price of the AIDS drug must be kept low. Most AIDS patients worldwide live in very poor countries. And many AIDS patients in developed nations are forced by the disease symp toms to leave their jobs. Known at present only as L-735,524, the Merck drug is an HIV protease inhibitor. It prevents protease-catalyzed cleavage of a viral protein precursor into smaller structural and regulatory proteins. Inter rupting this step in the virus life cycle could check the course of the disease. Vi ral protein cleavage is autocatalytic be cause one of the products is HIV protease itself. The protease then catalyzes further processing of viral proteins. HIV protease contains two identical polypeptide subunits with the active site at the junction between them. The Merck drug inhibits the enzyme by occupying the active site. Thus, any mutation in one
polypeptide of the HIV protease changes the active site identically on both sides, which can accelerate development of re sistance to the drug. To delay onset of such resistance, an HIV protease inhibitor must be unsymmetrical—different at each end of the molecule—so that it always binds to one part of the active site. The drug, which has five asymmetric carbon atoms, must also be a single enantiomer for optimal binding to the chiral active site. Seeking a low-cost robust process, Merck chemists and engineers devised a four-step sequence that couples three advanced intermediates they call "aminoindanol," "glycidyl," and "piperazine." An enantiomer of ris-l-amino-2indanol contains two asymmetric cen ters, which induce the correct asymmetry in two more centers. To keep costs down and avoid waste, Merck turned to Sepracor for enantioselective technology to make the single isomer of aminoindanol in the first re action from indene. Merck could not tolerate carrying a racemate through
several steps, followed by later resolution and wasteful discard of unwanted isomer. Sepracor has licensed the asymmetric epoxidation technology developed by organic chemistry professor Eric N. Jacobsen of Harvard University. This asymmetric epoxidation was successful in generating an enantiomeric epoxide, which could be converted via an oxazoline to the needed isomer of the aminoindanol. Sepracor is supplying catalysts for the Jacobsen reaction. Observers in the industry tell C&EN that DSM Andeno of Venlo, the Netherlands, is actually supplying the aminoindanol. Stephen Stinson
NSF gives urban science education $135 million Nine cities with large numbers of children living in poverty will each receive $15 million over the next five years from the National Science Foundation (NSF) to improve their science, math, and technology education. The awards are the first major grants under NSF's ambitious new Urban Systemic Initiative, which aims to catalyze sweeping changes throughout the cities' educational establishments. "It is fair to say that the nine awards represent a revolutionary vehicle to ameliorate one of the most intractable issues of our time/' says Luther S. Williams, NSF assistant director for education and human resources. "That is, to reduce the performance gap in science and mathematics between often poor, substantially minority inner-city youths and their cohorts in more affluent communities." "We expect to revise all elements of the status quo," Williams adds. "How the system is governed, how it's organized, [its] policies, finances, curriculum, teaching, assessment, and belief systems and attitudes as they relate to the abilities and interest of inner-city youth to learn science and mathematics." The nine cities—Baltimore, Chicago, Cincinnati, Dallas, Detroit, El Paso, Miami, New York, and Phoenix—are among the 25 eligible for the grants based on their number of poverty-level school-age children. The cities have been working with NSF for the past year to develop partnerships involving the city governments, school systems, parents, business communities, and local universities. These coali-
tions have committed to raising standards and expectations for students while providing teachers with necessary training and tools. The NSF education directorate's systemic reform movement also includes both a Statewide and a Rural Systemic Initiative. The common goal of all three programs, Williams says, is to stimulate sustained change in all facets of the science educational system. The programs are centered on the premise that a strong foundation in science and math is essential to the education of all children, not just the top students. New York City has already begun implementing the kind of change the NSF program wants to foment. It announced earlier this month that students will no longer be able to receive a high school diploma without rigorous course work in math and science. "The $15 million we're getting from NSF is not even above the noise level of the New York City school budget of $7 billion," says chemist Charles W. Merideth, president of New York City Technical College and a member of the city's systemic change team. "We see the money as a catalyst to jump-start our reforms." Pamela Zurer
Arco may sell stake in Lyondeli Petrochemical Atlantic Richfield Co. (Arco) has unveiled a plan to raise as much as $1 billion in cash by publicly offering debt securities linked to stock in Lyondeli Petrochemical. Arco owns slightly less than half of the Lyondeli stock. The plan would allow Arco, if it chooses, to divest itself of its 49.9% stake (39.92 million shares) in the Houstonbased chemical firm. Sale of the notes is tied to Lyondell's stock price of $25.25 per share on May 4. The debt securities will be exchangeable after three years, at Arco's option, into either Lyondeli common stock or cash. Betting is that Arco will exchange the securities for stock and divest itself of Lyondeli—joining other oil firms that have recently distanced themselves from chemical holdings to generate cash. In the late 1980s, Arco spun off its chemical operations into two publicly owned companies: Its integrated petrochemicals and petroleum processing
Lyondeli at a glance Sales: $3.9 billion in 1993 $4 million in 1993, excluding effects of accounting changes Headquarters: Houston mployees: 2,283 r products: Petrochemicals, including olefins (primarily ethylene, propylene, butadiene, butylènes, and specialty products), methanol, methyl tert-butyl ether, low-density polyethylene, and polypropylene Owns about 90% of LyondellCitgo Refining Co., which produces refined petroleum products, including gasoline, heating oil, jet fuel, aromatics, and lubricants units became Lyondeli, and its oxygenates and thermoplastics operations became Arco Chemical. Arco still owns more than 80% of Arco Chemical stock. Arco will not cite specific reasons for its new move, saying proceeds of the offering will be used for general corporate purposes. "Arco's plan to go forward with this debt offering has been motivated by Arco's financial strategy and does not reflect any adverse view of Lyondell's future," stresses Mike R. Bowlin, Lyondeli chairman and Arco president. "On the contrary, we have structured this transaction so that Arco can continue to participate in Lyondell's upside potential." Indeed, Arco is considering sale of its stake in Lyondeli at a time when the chemical business is showing signs of recovery. "Actions that Lyondeli took in 1993 to strengthen the company have improved Lyondell's outlook for 1994, even if industry conditions [were to] remain the same as they were in 1993," said Bob G. Gower, Lyondell's president and chief executive officer, at the firm's recent annual meeting. "However, so far the business environment for both petrochemicals and refining looks significantly better than last year." "We do not believe [Arco's proposed offering], if completed, will have any impact on [Lyondell's] operations," Gower added. The only real change will be reshuffling of board members. Five of Lyondell's 11 directors who are Arco officers will resign after close of the debt offering. Susan Ainsworth MAY 16,1994 C&EN
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