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Guest Commentary: Accelerating discovery through contract chemical synthesis
November 2016
by Dr. Jeremiah P. Malerich, SRI  |  Email the author
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Contract chemistry laboratories are playing an increasingly important role in drug discovery and development. These labs provide vital chemistry services, including resynthesis for hit validation, development of focused libraries to explore SAR (structure activity relationships) and designing libraries for lead optimization. Later-stage programs can benefit from scale-up of lead compounds for in-vivo experiments and preparation of metabolites and reference standards. Specialized laboratories deliver radiolabeled compounds to support ADMET and imaging studies. Experienced contract chemists partner from concept to development candidate, delivering consistent, efficient strategies for accelerating drug development. This article explores the role of contract chemistry in drug discovery.
 
Why contract synthesis?
 
Contract synthesis providers offer significant advantages to clients in three areas: (1) facilities, (2) staffing and (3) expertise. By using contract synthesis providers, small companies and startups can “act larger” than they are. Setting up even a bare-bones synthetic chemistry lab without modern analytical equipment is a costly and time-consuming process. Routine synthetic equipment such as NMR (nuclear magnetic resonance) and LC-MS (liquid chromatography–mass spectrometry) instruments may be prohibitively expensive and require experienced staff. Additionally, contract synthesis providers have established procedures for “the little things” (e.g. sourcing dry ice and liquid nitrogen or proper waste management) that may not be routine in small or startup companies. Contracting synthesis affords access to facilities, chemistry staff and resources with minimal capital investment and reduced risk.
 
The laboratory may have technical expertise in a molecule class or a synthetic reaction or have capabilities that the company itself lacks. There are many small or virtual companies that don’t have synthetic chemistry laboratory space and must use contractors for all synthetic operations. Staffing considerations also lead clients to use a contracting firm, since they may have limited synthetic staff whose efforts could be better utilized in their research role rather than a resynthesis. Larger companies benefit from partnerships with contract chemistry providers to temporarily increase throughput without the increased risk of taking on new staff or expanding facilities. Small companies stay nimble by keeping permanent staff small and focused.
 
In a custom synthesis program, the customer requests a specific compound and amount to be synthesized for them by a defined deadline. Requests can range from milligram (mg) to kilogram (kg) quantity in scale. Quantities larger than 10 kg are considered manufacturing and would be referred to a contract manufacturing organization. Syntheses can have precedent, or the client could request the firm design a synthetic route.
 
Contract chemistry laboratories may also have specialties. Some firms focus on the discovery phase of a program, providing medicinal chemistry support while others operate in the preclinical development phase, providing mg to kg scale-up efforts of known compounds for efficacy and toxicity studies. In all cases, the contract chemistry firm is flexibly staffed to dedicate immediate synthetic expertise to new programs, delivering the custom chemical to the client on budget, on schedule and of high quality. This flexibility, speed and dependability are the drivers of successful client-contractor partnerships.
 
What services do contract synthesis organizations provide?
 
For drug discovery, contract synthesis laboratories can expedite discovery by offering small-molecule medicinal chemistry support. These firms synthesize structurally diverse screening libraries for hit identification. The contracting laboratory also resynthesizes putative hits for validation. They provide focused libraries around a validated target to map preliminary SAR (structure-activity relationship). To advance research programs, the contracting firm can resynthesize an active compound for target identification and validation.
 
In hit-to-lead optimization, the contract firm provides synthetic libraries around a known hit scaffold to optimize efficacy. These are typically mg quantities for in-vitro screening assays. In programs where the target is unknown, SAR from an early focused library dictates structural modifications and helps guide the design strategy. For discovery programs with a known target and a crystal structure, contracting firms with computational chemistry capabilities can perform computer-aided drug design. In this approach, the firm designs focused libraries that optimize known or hypothesized electrostatic interactions of the small molecule within the enzyme’s active site.
 
After an active compound has been identified, it is submitted for ADMET (absorption, distribution, metabolism, excretion and toxicity) screening. These in-vitro screens measure properties that govern its bioavailability, such metabolic stability and cell permeability, as well as potential safety concerns such as CYP (cytochrome P450) or hERG (human ether-a-go-go-related gene) inhibition. If a compound has solubility or metabolic stability issues, the synthetic laboratory undertakes structural modifications to improve these properties. Contracting firms will also synthesize reference standards for these screening assays. They may also be asked to synthesize putative metabolites of active compounds as reference standards in metabolic stability screening and to determine the safety profile of known drug metabolites.
 
Once the lead compound has been identified, the drug candidate is evaluated in efficacy and safety models in vivo. The contracting firm can provide multi-gram scale-up synthesis providing the requisite material for the studies. In some instances, known routes may be revised or improved to deliver the required quantity. On identification of a development candidate, a process chemistry route that delivers kg quantities of the active pharmaceutical ingredient is required. A contract chemistry firm can be hired to perform route scouting, optimizing the synthesis for manufacturing considerations. General considerations for designing a process route include avoiding chromatographies, avoiding desiccants, avoiding volatile and chlorinated solvents, controlling temperature, avoiding protecting groups, controlling and characterizing known impurities and reducing synthetic steps and cost.
 
For a client with limited internal synthetic chemistry resources, outsourcing the work to a contracting chemistry partner liberates the client’s chemistry group to focus on their internal research thrusts. Since contracting firms operate in all phases of research and development, a contracting partner offers the ultimate flexibility for staffing and allocating resources to synthetic projects in the critical path. Firms that offer a range of these services can partner with a client from an early stage, adding value to a research program by obviating the need for costly and time-consuming technology transfer during preclinical development.
 
Radiolabeling
 
Isotopic labeling of a small molecule supports binding and imaging studies for drug development. Contract firms that specialize in radiolabeling can develop synthetic routes that combine the research needs of the partner with the known chemical synthesis and the availability of radiolabeled building blocks. Typically, the labeled building blocks are expensive, and strategies that incorporate the label at a late synthetic step are desirable as they reduce cost and limit the opportunity to scramble the isotope label.
 
Stable isotopes (e.g. 2H, 13C, 15N) are used to trace the fate of a small molecule in a biochemical pathway. Typically, compounds labeled with stable heavy isotopes are useful as analytical reference standards for mass spectroscopy since they provide a distinct signature or in NMR analysis where they can enhance the signal for a peak of interest. They can also be used as a chemical feedstock for the interrogation of a biochemical pathway such as enzyme catalysis or drug metabolism. In this application, the unique spectral features of the reference standard permit its use as an internal standard or to track chemical degradation by following the isotope label in the products of the biochemical transformation under study.
 
Unstable isotopes (e.g. 3H, 14C, 18F, 13N, 32P, 125I) have an associated half-life that dictates synthetic strategy. Some labels are extremely useful in bioimaging applications such as positron emission tomography (PET) imaging. For extremely short-lived isotopes, the labeling step should be the final step in the synthesis for viability. Longer-lived isotopes are used to radiolabel test molecules for pharmacokinetic studies and in enzyme binding assays. These labels must be placed in metabolically stable locations in the compounds.
 
A contracting firm will design the custom synthesis route and explore its feasibility with stable isotopes in what is termed a “cold run.” The methods from these studies will be transferred the “hot run” using the radiolabeled material. Firms that specialize in radiolabeled synthesis have a unique command of the design considerations, costs and availability of labeled building blocks to provide cost- and time-competitive strategies. In addition, they have the needed licenses, highly trained staff and specialized facilities. Partnering with a firm that does both drug development and radiolabeled synthesis can accelerate development through seamless technology transfer between synthetic groups. The intimate knowledge of synthetic pitfalls gained from the discovery chemistry group aids the synthetic design for the radiolabeled synthesis. This can improve yield and purity and decrease time to delivery, all qualities that benefit fast-paced research.
 
Noted above are the important ways a contract chemistry partner can accelerate drug development for commercial companies of any size. By offering skilled flexible staffing, dedicated synthetic resources and established infrastructure to support chemical synthesis, a contracting partner frees the client from the financial burdens and risks of building additional synthetic capacity in-house. By partnering with contracting firms that specialize in all phases of drug discovery and development, an established contractor/client relationship increases the pace and quality of delivery throughout a program by eliminating multiple costly and time-consuming technology transfers. As the complexion of small-molecule drug discovery in the industry evolves, contracting firms will increasingly provide pivotal services and capabilities that allow a private partner to focus on their critical path accelerating the delivery of novel drugs into the clinic.

The authors of this paper are Dr. Peter B. Madrid, director of discovery technologies for SRI International; Dr. Jeremiah P. Malerich, program director for synthetic and medicinal chemistry at SRI; Dr. Mary J. Tanga, senior director of synthetic and medicinal chemistry for SRI; and Dr. Ellen Beaulieu, assistant professor of chemistry at Diablo Valley College in California.

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