Building Toolboxes in Pursuit of Single-Enantiomer Drugs - Pharmaceutical Technology

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Building Toolboxes in Pursuit of Single-Enantiomer Drugs
Biocatalysis, chemocatalysis, and other chiral technologies continue to attract the investment dollars of CMOs and fine-chemical companies.


Pharmaceutical Technology
Volume 35, Issue 9, pp. 54-58

The initial (R)-selective transaminase was a homologue of an enzyme from Arthrobacter sp., which previously was used for (R)-specific transamination of methyl ketones and small cyclic ketones. For the sitagliptin synthesis, the researchers generated a structural homology model of this transaminase and found that the enzyme would not bind to the prositagliptin ketone because of steric interference and potentially undesired interactions. The evolved transaminase was a successful biocatalyst that synthesized the chiral amines that previously were accessible only through resolution (1–3).

Codexis and Merck were recognized in 2010 with an Environmental Protection Agency's Presidential Green Chemistry Challenge Award, an annual recognition of advances in green chemistry. Codexis also submitted for consideration in 2010 and 2011 a biocatalytic route for making simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug Zocor, which is now off patent (3, 4).

Codexis licensed technology from Yi Tang, professor in the department of chemical and biomolecular engineering at the University of California at Los Angeles. The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolyzed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride, and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2 carbon with methyl iodide, and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (3).

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste, and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by Aspergillus terreus that is involved in synthesizing lovastatin and that can accept nonnatural acyl donors. Recognizing that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (3–5). Codexis licensed Tang's technology, engineered the enzyme further, and optimized the process for pilot-scale simvastatin manufacture. During 2010, Codexis scaled up enzyme manufacture to the 150-kg batch scale and manufactured simvastatin ammonium salt in 400-kg batches (4).

In June 2011, the biocatalysis company Enzymicals launched a screening kit for (R)-selective transaminases. Techniques for the recombinant production of (R)-selective transaminases were developed under a collaboration with Lonza. The enzymes can be used in the synthesis of chiral amines and other chiral intermediates. Process patents for transamination also are included in the license agreement, which allows Enzymicals to carry out customer-oriented laboratory testing. Enzymicals was founded in August 2009 by the research group of Uwe Bornscheuer, professor in the department of biotechnology and enzyme catalysis in the Institute of Biochemistry at Ernst Moritz Arndt University in Greifswald, Germany. In addition to (R)-selective transaminases, Enzymicals also offers other proprietary biocatalysts, such as PLE isoenzymes, several esterases, and Baeyer–Villiger-monooxygenases.

In November 2010, W.R. Grace completed its $19.2-million acquisition of Synthetech, a manufacturer of fine chemicals, specialty amino acids, and chiral intermediates, including capabilities in biocatalysis. W.R. Grace acquired Synthetech's prodction and R&D facility in Albany, Oregon, and a second R&D facility in San Diego.

In July 2010, Johnson Matthey acquired X-Zyme, a provider of enzymes, particularly oxidoreductases for producing chiral intermediates. X-Zyme is a 2001 spin-off from Heinrich Heine University's Institute of Molecular Enzyme Technology in Germany. X-Zyme's portfolio included enzymatic catalysts for scalable production of highly pure chiral amines and alcohols. And in March 2010, Cambrex acquired IEP, an industrial biocatalysis company in Wiesbaden, Germany. Cambrex gained IEP's capabilities in customized biocatalytic process-development and enzymes for pharmaceutical applications.


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