Building a Successful Crop Protection Pipeline: Molecular Starting

Chapter 2

Building a Successful Crop Protection Pipeline: Molecular Starting Points for Discovery Downloaded by UNIV LAVAL on November 7, 2015 | http://pubs.acs.org Publication Date (Web): November 4, 2015 | doi: 10.1021/bk-2015-1204.ch002

Kathleen A. Shelton* and George P. Lahm* DuPont Crop Protection, Stine-Haskell Research Center, Newark, Delaware 19711, United States *E-mail: [email protected]; [email protected]

The discovery and development of new products for crop protection begins with a healthy pipeline of molecular starting points for discovery. Strategies and processes associated with the identification of new starting points will be discussed.

Protection of the global food supply is essential as world population grows from approximately seven billion today to an estimated nine billion people by the year 2050. Global food protection will take the combined efforts of industry, government, farmers and a host of others that influence world food production. The stakes are high and incorporate enormously large issues such as efficient management of land and water. Crops will further require continued protection from the pressures of disease, insects and weeds that seek to compete. The changing dynamics of pest populations and the development of resistance are among some of the factors that demand new innovation and new technology for farmers the world over. The health of the crop protection industry as well as a crop protection business is directly then related to its new product pipeline. A healthy pipeline insures a renewable source of new products for plant protection and provides the farmer new tools to meet changing needs. It further aids in the combat of pest resistance through the support of resistance management strategies that frequently employ rotation of products acting by differing modes-of-action. At DuPont we recognize that for the health of our own Crop Protection business it is essential that we provide a consistent stream of new products into our pipeline. We have clearly defined “product concepts” focused on critical success factors, including customer needs, societal needs and regulatory requirements. © 2015 American Chemical Society In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

Downloaded by UNIV LAVAL on November 7, 2015 | http://pubs.acs.org Publication Date (Web): November 4, 2015 | doi: 10.1021/bk-2015-1204.ch002

Our goal for a new crop protection product is to create a new molecule that has attributes beyond what is currently on the market. Depending on the product and the market, our search for new products will be molecules that provide some combination of the following: an improvement in pest control, enhanced toxicological or environmental profile, differentiating attributes (e.g. fast acting, improves yield, quality, etc.), or provides a new tool in integrated pest and resistance management. The identification of new crop protection products begins with the identification of new molecular starting points (Hits). Typical new starting points are generally weakly active on the pest and little is known of their profile with respect to a host of parameters including spectrum as well as their environmental and toxicological profiles. Once identified, however, the optimization of chemistry through the judicious choice of synthetic analogs, coupled with a feedback loop for new analogs based on evolving structure-activity profiles, can lead to exquisitely active compounds with well understood ecological and toxicological profiles. The course of optimization frequently requires solutions to a variety of issues and our experience shows that only a small fraction of molecular starting points are successfully optimized to new products. It is essential, therefore, for any successful crop protection pipeline to identify and maintain a healthy and robust supply of new starting points. The pipeline in principle then begins first with identification of new Hits. We operate on the principle that a balanced approach to the discovery of new molecular starting points is essential and focus on three main streams of input (Figure 1).

Figure 1. Primary streams of input for chemical starting points

16 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


1.

2.

3.

High Volume Sources (HVS) provide a rich supply of new molecules for screening. Over the years we have refined our selection algorithms to maximize the diversity of the compounds acquired and fill gaps in our existing compound libraries. To further increase the chances of success, a variety of algorithms have been developed to seek compounds with “Ag-Like” properties in keeping with rules such as those from Lipinski and Tice as well as proprietary models developed internally. Independent analysis of properties associated with the diversity of active crop protection chemistry gives additional insight into compounds and compound libraries we might acquire. Related to our high volume sources are the million plus compounds we have in our in-house chemical libraries. These serve as a rich source of chemistry as the insecticide, fungicide and herbicide screens evolve in testing protocols or change as new species are added. The addition of high volume screens further allows re-testing (retro-screening), or in some instances first time testing, of compounds designed for a specific set of screens (e.g. herbicides) that have yet to be screened broadly. Over time we have seen numerous examples of compounds designed to control one particular area will show surprising activity on another and the literature supports that this is not an uncommon occurrence. Chemistry-Based Discovery (CBD) is a term we use to describe new Hits identified through the knowledge and intuition of our scientists based on inspiration from known molecular starting points. The enormous volume of information that provides clues to biologically active molecular entities makes this a particularly challenging task as one must choose a starting point for ideas. The ideas of course must ultimately be reduced to practice, i.e. a molecule that can be screened and tested. Information provided through patents, journals, meetings and other sources of knowledge such as natural products or the pharma literature along with a rich source of in-house data on millions of biological tests afford a multitude of inputs for information to be distilled. The aid of computational tools and the input of colleagues provide a valuable source of added insight and grounding. Target-Based Discovery (TBD) has proven to be a useful tool in the identification of new molecular starting points and a variety of interesting new molecular types have been discovered. Issues associated with translation (i.e. the translation from in vitro to whole organism activity) have however proven to be a vexing problem. The issue is in fact two-fold. First, at this point in time the percentage of successful Hits we have identified through Target-Based Discovery is significantly lower than those identified either through Chemistry-Based or High-Volume strategies. Second, for those Hits that have been successfully identified we have yet to realize an advanced pipeline candidate, let alone a new product. Nevertheless, we continue to seek to solve this problem as we believe the strategy has great value if translation issues can be resolved. Chemistry to biochemical mechanism is a related approach that first relies on the identification of a new molecular starting point followed by 17 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


identification of the biochemical mechanism of action. It is not unusual to find that many of the new Hits which show activity in the crop pest screens act by known biochemical mechanisms. These are determined through a panel of tests designed to evaluate known modes-of-action for existing Hits and Leads. However, in the rare instances where new biochemical modes-of-action are identified, the establishment of in vitro screens can be a valuable tool in the search for new molecular starting points. These starting points typically face the same issue of translation but have the advantage of being coupled with validation that the particular mechanism can express in vivo pest activity based on knowledge of the original Hit. Within any of the three discovery platforms described above we find the common thread that drives innovation is the people associated with discovery. At DuPont we are fortunate to have a highly experienced staff with a broad knowledge base of the crop protection business. We allow for a free flowing exchange of ideas and seek to provide training and experience for all of our discovery scientists across all indication areas. As we hire new employees we further set up long term mentoring relationships to insure the knowledge base is passed on. Some of the attributes associated with the scientific staff that we believe hold high value include the following: • • • • • • •

Knowledge: Possess deep knowledge in the field of technology, the underlying science, and the associated business Creativity: Ability to bring seemingly disparate pieces of information together to create something new Perseverance: Ability to work through problems and to know when to stop pursuing an idea and shift to a more promising course Team oriented: Ability to work within groups and across functions Externally focused: Ability to garner support for ideas and engage the best resources Market focused: Possess a clear understanding of product concepts, customer needs and market opportunities Know the competition: Have a thorough understanding of the competitive landscape and the patent landscape.

The examples that follow serve to illustrate some of the strategies used in the discovery of new molecular starting points. In the first example we highlight the High Volume Source strategy (Figure 2). The initial Hit for the new fungicide oxathiapiprolin (DuPontTM ZorvecTM) was discovered through the screening of a 300 plus combinatorial library acquired from Tripos. The library was composed of diamides derived from 4-thiazolylpiperidinecarboxylic acids. While there was very little activity detected for the library as a whole, one compound (DP-010) was found to demonstrate some activity on grape downy mildew and in particular showed modest levels of curative control. Further, DP-010 was the only compound that contained both phenyl acetamide and benzyl amino substituent groups making it a unique chemotype within the library. Synthesis of a subset 18 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


of analogs confirmed oomycete activity for a wide spectrum of compounds with derivatives derived from pyrazole acetamides showing the most promise. Further constraining of the 2-methylbenzylamino group into a 2-aminotetralin produced the analog DP-020 which showed a 1000-fold improvement in biological activity with good curative control. Extensive optimization through over 1200 analogs led to the discovery of oxathiapiprolin, the most potent oomycete fungicide to date with remarkable preventive and curative activity (1–3).

Figure 2. High Volume Sourcing Strategy, Zorvec® Fungicide

Important lessons here come not only from the confirmation of High Volume Sources as a valuable strategy but also to the importance of critical evaluation of the biological data and the keen insight required to extract a weakly active Hit from an otherwise inactive library. It would have been easy to dismiss the initial Hit given that activity was found for only a single analog. The next example stems from a discovery made in the retro-screening of our in-house libraries leading ultimately to the new insecticide triflumezopyrim (Figure 3). This strategy is a form of directed High Volume Sources where random screening is intended to fill in data gaps, test on new species or seek internal compounds with specific physical properties. The compound DP-030 was found to possess moderate levels of activity on both lepidopteran and hemipteran pests. It was determined that these compounds acted by a new mechanism at the nicotinic receptor with good activity on pests resistant to neonicotinoids. While the traditional chloropyridyl and chlorothiazolyl heterocycles demonstrated good activity it was observed that the unsubstituted thiazoles provide better hopper control. Extending this observation into other heterocycles we found that the unsubstituted pyrimidine of triflumezopyrim stood out. Triflumezopyrim is in fact the most potent compound discovered for the control of planthopper pests in rice with outstanding activity in both contact and systemic applications (4–6). 19 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 3. Retro-Screening of Internal Compound Files, Triflumezopyrim Insecticide

Another rich source of Hits and Leads comes from a strategy directed toward the design of novel chemistry based on knowledge extracted from the expansive pool of chemical and biological information found in the open literature and internal sources, i.e. Chem-Based Design (Figure 4). The publication of insecticidal activity associated with a new class of phthalic diamides by Nihon Nohyaku prompted exploration in adjacent chemical spaces including anthranilic diamides. We were able to identify modest levels of activity on important lepidopteran species for anthranilamides such as DP-040 which provided our initial internal molecular starting point for optimization. At the outset, the other interesting observation was that the biochemical mechanism was not identified in our mode-of-action panels suggesting that the mode-of-action was new. Through a two year program aimed at optimization of the chemistry we were able to identify a potent class of pyridylpyrazole anthranilic diamides on a wide spectrum of Lepidoptera. We further determined these compounds worked through inhibition of the ryanodine receptor, a novel mode-of-action for synthetic insecticides first identified for the natural product ryanodine. From this group of pyridylpyrazole anthranilic diamides, chlorantraniliprole (Rynaxypyr®) was found to possess the optimum properties for exceptional pest control. Rynaxypyr® has proven to be a remarkable product for farmers around the world (7–9).



Figure 4. Chem-Based Discovery, Rynaxypyr® Insecticide

The final example is an extension of Chem-Based Discovery in the search for molecular starting points through physical property modification of existing leads or products (Figure 5). As noted above, chlorantraniliprole was found to be exceptionally active on lepidopteran pests. While there were indications of activity on a broader pest spectrum, including insects from the order Hemiptera, the lack of significant systemic activity precluded significant utility in this market. In an effort to improve systemicity, compounds with improved aqueous solubility, as measured by reduction of their calculated log P, were examined. After the evaluation of approximately 1500 analogs it was determined that introduction of a cyano group as a replacement for chloro on the anthranilic ring provided a range of compounds with improved systemic properties and with broad activity over a wide spectrum of lepidopteran and hemipteran pests with cyantraniliprole (Cyazypyr®) as most preferred. In the particular case of Cyazypyr® the measured logP was found to drop a full log unit as compared to Rynaxypyr® and this reduction in logP is largely responsible for the improved systemic properties. Obviously, it was particularly important that activity be retained for compounds with reduced logP as we worked through many modifications that improved water solubility but simultaneously lost activity. Cyazypyr®, in its second full year of sales, promises to be an exceptional product for cross-spectrum pest control (10, 11).



Figure 5. Physical Property Modification, Cyazypyr® Insecticide

Critical Success Factors for New Product Commercialization In addition to the technical challenges of discovering new crop protection chemicals, at DuPont we believe that the governance of the process is critical to the overall success of the technical effort. Within the business we charter decision boards with cross functional business representation, including marketing, supply chain and business development, in addition to research and development. The purpose of the decision boards is to have a holistic view of the end to end process from discovery to commercialization. The decision boards are accountable for oversight of the Staged-Gated process that works collaboratively with R&D to manage the discovery & development pipeline, including assessing the market opportunity and value of the new crop protection products. The decision boards also enable strong collaboration between R&D and marketing to occur throughout the development process, ensuring that the new product is meeting a market need that is valuable to the grower and is aligned with our product concepts. With all the tools we have developed and teams we have chartered, the success and value of our pipeline is truly the output of the people who work in our research and development organization. Discovering and developing a new crop protection products takes years, sometimes almost a decade of effort and dedication. Ultimately, our success lies with the people who dedicate their time to this goal, who bring their creativity, their technical skills, and are empowered with a strong sense of urgency to achieve our goals. No one person or team can achieve this goal, and our team members work in and sustain collaborative team environments equipped with the necessary tools and processes to get the job done.


References Pasteris, R. J.; Hanagan, M. A. Abstracts of Papers: 13th IUPAC International Congress of Pesticide Chemistry; San Francisco, CA, United States, August 10−14, 2014. 2. Pasteris, R. J.; Hanagan, M. A.; Bisaha, J. J.; Finkelstein, B. L.; Hoffman, L. E.; Gregory, V; Sheperd, C. P.; Andreassi, J. L.; Sweigard, J. A.; Klyashchitsky, B. A.; Henry, Y. T.; Berger, R. A. In Discovery and Synthesis of Crop Protection Products; ACS Symposium Series 1204; Maienfisch, P., Stevenson, T. M., Eds.; American Chemical Society: Washington, DC, 2015; Chapter 13. 3. Pasteris, R. J.; Hanagan, M. A.; Shapiro, R. World Patent WO 2008013925, 2008. 4. Holyoke, C. W.; Zhang, W.; Pahutski, T. F., Jr.; Lahm, G. P.; Tong, M.H. T.; Cordova, D.; Schroeder, M. E.; Benner, E. A.; Rauh, J. J.; Dietrich, R. F. Abstracts of Papers: 13th IUPAC International Congress of Pesticide Chemistry; San Francisco, CA, United States, August 10−14, 2014. 5. Holyoke, C. W.; Zhang, W.; Pahutski, T. F., Jr.; Lahm, G. P.; Tong, M.-H. T.; Cordova, D.; Schroeder, M. E.; Benner, E. A.; Rauh, J. J.; Dietrich, R. F. In Discovery and Synthesis of Crop Protection Products; ACS Symposium Series 1204; Maienfisch, P., Stevenson, T. M., Eds.; American Chemical Society: Washington, DC, 2015; Chapter 26. 6. Pahutski, T. F., Jr. World Patent WO 2012092115, 2012. 7. Lahm, G. P.; Selby, T. P.; Stevenson, T. M. World Patent WO 03/015519, 2003. 8. Lahm, G. P.; Stevenson, T. M.; Selby, T. P.; Freudenberger, J. H.; Cordova, D.; Flexner, L.; Bellin, C. A.; Dubas, C. M.; Smith, B. K.; Hughes, K. A.; Hollingshaus, J. G.; Clark, C. E.; Benner, E. A. Rynaxypyr™: A New Insecticidal Anthranilic Diamide that Acts as a Potent and Selective Ryanodine Receptor Activator. Bioorg. Med. Chem. Lett. 2007, 17, 6274–6279. 9. Lahm, G. P.; Selby, T. P.; Freudenberger, J. H.; Stevenson, T. M.; Myers, B. J.; Seburyamo, G.; Smith, B. K.; Flexner, L.; Clark, C. E.; Cordova, D. Insecticidal Anthranilic Diamides: A New Class of Potent Ryanodine Receptor Activators. Bioorg. Med. Chem. Lett. 2005, 15, 4898–4906. 10. Selby, T. P.; Lahm, G. P.; Stevenson, T. M.; Hughes, K. A.; Cordova, D.; Annan, I. B.; Barry, J. D.; Benner, E. A.; Currie, M. J.; Pahutski, T. F. Discovery of Cyantraniliprole, A Potent and Selective Anthranilic Diamide Ryanodine Receptor Activator with Cross-Spectrum Insecticidal Activity. Bioorg. Med. Chem. Lett. 2013, 23, 6341–6345. 11. Hughes, K. A.; Lahm, G. P.; Selby, T. P.; Stevenson, T. M. World Patent WO 04/67528, 2004.


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Building a Successful Crop Protection Pipeline: Molecular Starting

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