COVER STORY GENESIS Molecular modeling aids the search for druglike compounds.
comer Onyx Scientific hopes to complete a new chemistry unit and recruit up to 12 additional bench chemists by year's end. Estimates of the total market for this custom synthesis segment vary, but $400 million, or 1% of pharmaceutical R&D spending, "is probably a good ballpark figure," says Gareth Jenkins, business development manager at Peakdale Molecular. In 2001, member companies of the Pharmaceutical Research & Manufacturers of America spent about $30.3 billion in R&D.
CUSTOM SYNTHESIS FOR DRUG DISCOVERY Companies providing exclusive synthesis for early drug development are upbeat about 2003 A. MAUREEN ROUHI, C&EN WASHINGTON
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HEN FEW NEW DRUGS ARE
launched, big custom manufacturers of advanced intermediates and active ingredients are hit badly, as they were in 2002. But because research in pharmaceutical companies must go on—to discover new drugs and feed the development pipeline—providers of exclusive synthesis for the early phases of drug development fared better than custom manufacturers in 2002. Business, though slower, allowed gains over the previous year and expansions of operations. The outlook for 2003 is optimistic. "The worst is over now," saysThomas E. D'Ambra, chiefexecutive officer of Albany Molecular Research (AMR), which provides custom chemistry services for drug discovery and development. AMR did well in 2002, but it wasn't easy Chemistry custom services are estimated to have brought in sales of about $73 million in 2002, up 28%from2001.TThat growth was achieved despite AMRs loss of a long-term contract early last year when DuPont Pharmaceuticals was acquired by Bristol-Myers Squibb, D'Ambra says. "We had to hustle just to stay even and then grow on top of that." D'Ambra believes that the belt-tightHTTP://WWW.CEN-ONLINE.ORG
ening of the pharmaceutical industrydue to expiring patents on blockbusters, disappointing sales of new products, unmet Wall Street expectations, and aborted launches—has peaked and drug companies will not cut R&D any further. He offers Eli Lilly as an example of a company poised to have a great 2003 and beyond. The company lost a major revenue stream when generic versions of its blockbuster drug Prozac became available. But now, several of its New DrugApplications have been approved or are pending approval. Companies are gearing up for the recovery of the pharmaceutical industry Reflecting the high demand for novel compounds for drug discovery, several companies based in England are expanding. At Tripos Receptor Research (TRR), construction is underway to more than double laboratory space to 65,000 sq ft by 2004. Key Organics is adding lab space, expanding its compound-handling facility, and planning to hire up to 15 Ph.D. chemists in 2003. Peakdale Molecular will add two labs by April and will be hiring as many as 12 chemists by spring. And new-
THE MARKET'S RAPID growth means double-digit rises in revenues not only among major players, but also among smaller companies. Jenkins says Peakdale Molecular's sales are growing at least 50% per year. Likewise, Onyx Scientific has grown by leaps and bounds since its inception in June 2001 -with sales of about $400,000 in 2001 and about $3.5 million in 2002. The company expects sales to hit $6 million in 2003, CEO Tony Flinn says. Drug discovery begins with a validated target, usually a protein that regulates the progression of a disease. Genomics and other technologies are yielding a plethora of targets, but most of these are not associated with a known ligand. The goal of discovery research is a compound that will bind to the target and influence disease progression. To identify a chemical starting point, drug companies screen the target against vast numbers of structurally diverse compounds. If the structure of the active site is known, the initial screen can be done computationally, or "in silico." The goal of screening is to find "hits." These are compounds that are active in a screen; that is, they bind to the target in a manner that meets specified criteria. "A hit only gives you an idea of the drug molecule," explains Padmakumar R. Kaimal, director of discovery chemistry at Synthon Chiragenics. A hit rarely has the right combination of activity, selectivity, and bioavailability required of a drug. The structure has to be tweaked for maximum bioactivity and a desirable ADMET (adsorption, distribution, metabolism, excretion, and toxicity) profile. This tweaking produces "leads," which are compounds with properties that suggest their value as potential drug candidates. C & E N / F E B R U A R Y 17. 2003
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COVER STORY Alead is tested in an animal model ofthe disease to prove that it works and does not have adverse activity such as carcinogenicity, teratogenicity, or mutagenicity, Kaimal explains. The pharmacological properties of the compound are also established during animal testing. Data are obtained regarding the compound's pharmacokinetics—the fate of the compound when ingested, how long it is retained in the body, and what metabolites are formed—and pharmacodynamics —what happens to the body when the compound is ingested, for example, whether tumors are formed. CHEMICAL VARIATIONS ofalead are usually designed to generate compounds with optimal pharmacological properties. This process is called lead optimization. A compound that is both effective and safe in animal models becomes an investigational new drug (IND), or a drug candidate. In the U.S., an IND application must befiledwith the Food & DrugAdministration to move a drug candidate into human clinical trials. Numerous compounds ofdiverse structures are designed, prepared, and tested to arrive at one candidate. Pharmaceutical
OVERHEARD
What Customers Seek
C
&EN talked with outsourcing decisionmakers in the pharmaceutical industry. As the following excerpts show, the extent and requirements of custom synthesis vary with the drug development stage and the type of customer. Steven M. Hutchins, director of outsourcing in the research operations department at Merck, on outsourcing drug discovery chemistry: "The most important attribute that we look for in a collaborator is staff expertise for the project at hand. Once the collaborator has been selected, the big key to success is communication. It has to be frequent, open, and honest. If there are hitches in a project, we want to know. We've been in situations where things haven't gone well because the other company thought it had to try to solve all the problems. They didn't bring the problems
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out in the open so that we could both work as a team to try and solve them. "Companies that offer custom synthesis from milligram to ton scales typically are very good at one end of the scale but not the other. We work with a couple of onestop shops because we think that discovery is their forte. I've compared notes with my counterparts in manufacturing. I don't think we have identified one one-stop shop that we all want to work with. Being a onestop shop is not an advantage per se." loannis I. Valvis, group leader, sourcing strategy and capacity management for process R&D at Bristol-Myers Squibb Pharmaceutical Research Institute, on outsourcing chemical process development: "At this stage, we're still trying to understand the process and we're focused on putting together a supply chain that will provide high-quality active ingredients. It
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is at this stage that quality requirements for the product are set. For this reason, the most important criterion in vendor selection is the track record for producing rightquality material. We qualify suppliers based on performance, not price. "I will go to vendors that can take the manufacture all the way to commercialization. Getting involved early with such a vendor saves time and ensures product quality." Joseph R. Colleluori, director of strategic outsourcing for Merck & Co., on outsourcing manufacturing: "Outsourcing is decided on a project-byproject basis. Historically, Merck has awarded business to companies that have done business with us and have met our criteria of cost, competence, and creativity. We prefer suppliers that can provide us with materials through the life cycle of the product, from the early phase of clinical development, to launch, to product maturity. "Our sourcing decisions are based on many criteria, including technology, innovativeness, facilities to handle complex oper-
ations, provisions for catastrophic occurrences, capital resources for innovation, cost competitiveness, respect for intellectual property, and commitment to Merck's business." Daniel D. Burgess, chief operating officer of Hollis-Eden Pharmaceuticals, San Diego, Calif., on selecting a manufacturing partner: "Several factors made one medium-sized custom manufacturer in Portugal come out on top when we interviewed different companies to supply the active ingredient for a drug candidate. They had a good process development group, they understood the needs of a small biotech company in terms of flexibility and timing, and they were willing to work with us to develop a product. "We looked at companies bigger and smaller than the one we chose. The most important consideration from our perspective was being confident about their expertise in process development and scale-up. We got very comfortable that our selected company had the capability and systems in place to be a reliable long-term partner."
companies cannot prepare all the compounds for all their discovery programs. Outsourcingfillsthe gap. Merck, for example, contracts out medicinal chemistry and synthesis of libraries, reagents, scaffolds, and lead analogs, according to Steven M. Hutchins, director ofoutsourcing in the research operations department at Merck. Companies supplying compounds for drug discovery usually are generalists in their chemistry, synthesizing compounds that above all are unique and medicinally relevant. Differentiation comes in various ways. AMR has expertise in biocatalysis, natural products, and asymmetric synthesis, developed from its own R&D. Developing technology that can be licensed to customers is a plank ofthe business. For 2002, AMR will receive about $50 million in royalties from Aventis for licensing AMR patents related to the allergy drug Allegra. "That's a great example of the power you can bring to the bottom line from owning technology," D'Ambra says. Ricerca Biosciences is tapping into highquality but low-cost synthesis through a partnership with gvk bioSciences, a drug discovery and development company
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C & E N / FEBRUARY 17. 2003
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COVER STORY based in Hyderabad, India. "We have access to up to 100 medicinal chemists GROWING in India," Ricerca CEO Prabhavathi Fer- Key Organics exploits little-used chemistry nandes says. "We do the design here and to make unique screening compounds then send the compound over. The arrangement gives us a price advantage." One of Ricerca's strengths, Fernandes says, is awareness on behalf of the client. For example, Ricerca keeps an eye on a compound's polymorph form, υ a solid-state property that affects ΗΟ-Νγ^ bioavailability. If there is more than one Cl form, Ricerca alerts the client and designs a chemical process that generates the preferred polymorph.
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AWARENESS IS also expressed in valuable advice. For example, Fernandes discourages use ofultrapure compounds in very early toxicological studies, because the level of purity may not be attainable in scale-up and the toxicological studies would have to be redone. On the other hand, she advises clients to start process design as soon as a compound starts to look good in toxicology, because the impurities in one route may be different from those in another route. "In most cases, it's not expensive to improve the process. If anything, it is probably cheaper in the long run, as process changes can result in changes in polymorph form as well as in impurities," she says. TRR says it weds chemical informatics to bench chemistry to deliver compounds of high biological relevance in a short time. The goal is achieved through constant dialogue between molecule designers and bench chemists, who are supported by powerful software. Compounds of interest are identified by using ChemSpace, developed by TRR's parent, Tripos, a chemical informatics company Using ChemSpace, designers create a virtual library of druglike compounds that are similar in shape to a lead structure. Chemists prioritize the library members on the basis of medicinal relevance, feasibility of synthesis by highthroughput robotic methods, amenability to standard analytical techniques, availability of reagents, and whether the compound type is already in the market or in TRR's screening collection. The designer takes the information and refines the compound set. The dialogue goes back and forth until a working library is designed and eventually prepared. "I don't believe molecular modeling can be separated from the wet lab," TRR Director Peter Hecht says. "Informatics-driven chemistry needs to take into account what is possible not only in silico, but also 78
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scale synthesis ensures that the compound is in stock whenever the customer needs it, says the company's director, Colin Deane. It also means that every compound comes with a synthesis that is amenable to scale-up, adds Roger Moses, the company's principal chemist. Key Organics is known for heterocyclic chemistry That more than 80% of its 34,000-compound screening collection are heterocyclics reflects the great interest in this chemistry Deane says.
ONE WAY the company comes up with unique and novel structures is to dig through the literature for interesting but little-used chemistry Moses gives as an example iV-hydroxy-2-oxopropionimidoyl chloride, for which a practical synthesis was reported in 1968. He OCH3 says that at the time he was exploring /CH 3 how to use this reagent, he found only CH—N^ / ^CH 3 five examples in the literature. CH,0 Moses says he used the reagent in [3 +2} cycloadditions for a range of alkenes Cl synthesized by Key Organics chemists. And the products were further functionalized. 'All in all, I made some 34 compounds via this strategy," he tells N—CH, C&EN. / Peakdale Molecular also relies on "one-at-a-time custom synthesis, almost handcrafting the molecule," Jenkins says. The company is strong in heterocyclics, especially nitrogen heterocyclics, as well as carbonylations at unusual positions in the molecule. "That helps us access novel intermediates that drug companies are interested in." Meanwhile, Onyx Scientific is focused on traditional medicinal chemistry making analogs and helping develop a lead. On the basis of this strength, the comin vitro. Otherwise, you will have this won- pany is looking atrisk-sharingarrangements, derful solution that looks great on your whereby it will offer reduced rates for its screen but is completely unsynthesizable." chemistry services in exchange for royalties Another key tool at TRRis ChemCore, if a project is successful. Although only a a chemical-synthesis tracking database. very small part ofthe business could be done Not only does ChemCore track the avail- on that basis, Flinn says the company is conability of reagents, an important factor in sidering the arrangement as another way to early delivery, it also tracks compounds increase the value of the business. Thinking back on 2002, a bleak year from inception to delivery By capturing all the information associated with a com- indeed, D'Ambra says: "If you go back to pound in a database that can be searched 1992, that was the year of the health care by various criteria—structure, substruc- reform debate. For thefirsttime, the drug ture, structure similarity, name, generic industry laid off workers and cut back rename, acronym, reactions, products, and so search. We're reaping what happened at on—ChemCore enhances productivity the bench then. But the good news is that by the mid-1990s, R&D spending had and gets compounds to customers faster. Meanwhile, at Key Organics, chemistry picked up phenomenally Alot ofnew drugs is carried out in gram scale in glass vessels one are in the clinic right now and will be hitreaction at a time, instead of simultaneous- ting the market in 2004, 2005, and bely in 96-wellplates in milligram scale. Gram- yond. The boom is going to come back." •
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