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© Institut Pasteur
Cristaux de cellulase, enzyme purifiée de Clostridium thermocellum permettant la digestion de la cellulose. Image colorisée.

About

Medicinal chemistry in an academic environment: removing “chemical blind spots” Yves L. Janin

The task of doing good MedChem in an academic environment has been the subject of two recent comments which provide excellent illustrations of the issues involved in such endeavor (1,2). In the last decade, we have attempted to address some of these issues by providing our modest expertise in the domain and we also oriented our research in organic chemistry toward removing “chemical blind spots” existing in the chemical space of drug-like compounds. Our most advanced project was based on the observation that if there is a great number of pyrazole-5(2H)-ones described in the literature and patents (resulting from the use of the Knorr reaction), there are much less examples of pyrazole-3(2H)-one derivatives. From a simple process to prepare alkoxypyrazoles (3) we set to lessen this difference and prepared quite a few libraries of new chemical entities (4-13). So far, out of this ground work, an antiviral screening campaign, made on the CBC platform at the Institut Pasteur, led to an original series of strong inhibitors of human dihydroorotate dehydrogenase (14) which are illustrated by compounds 1 and 2 (15,16).

Scheme YJ3We are also working on the design of original bacterial type IIA topoisomerases via rescaffolding strategies. The last two decades have seen very important efforts, made by the pharmaceutical industry (17), to discover new antibacterials. If many news series of strong inhibitors of type IIA topoisomerases have been reported (18), they are yet to be used as antibacterials (19). From the wealth of structural data describing the binding modes of these inhibitors to bacterial type IIA topoisomerases (18), we are trying to design and synthesize original series which may overcome some of the problems encountered while trying to develop these compounds into actual antibiotics.

Finally, we became aware of the deep sea bioluminescent creatures luciferins such as coelenterazine or “varguline” (the luciferin of Vargula hilgendorfii) as well as many artificial analogues which found extensive uses in biology, including high-throughput screenings.

Scheme YJ2Interestingly, if an array of synthetic pathways to prepare such imidazopyrazines have been reported (20), we believe that, as for pyrazole chemistry, a chemical blind spot is existing in pyrazine chemistry. We should be reporting in the future in a project aiming at lifting this and, as for the alkoxypyrazoles, we hope that amongst the original compounds made in the course of this work some will turn out to display biological effects of interest in the screening campaigns made at the Institut Pasteur.

 

Thank you for reading

Yves L Janin

Bibliography

(1) Baell, J.; Walters, M. A. Chemical con artists foil drug discovery. Nature 2014, 513, 481-483.
(2) Baell, J. B. Screening-Based Translation of Public Research Encounters Painful Problems. ACS Med. Chem. Lett. 2015, 6, 229-234.
(3) Guillou, S.; Bonhomme, F. J.; Janin, Y. L. An improved preparation of 3-alkoxypyrazoles. Synthesis 2008, 3504-3508.
(4) Coutant, E. P.; Janin, Y. L. A study of Negishi cross-coupling reactions with benzylzinc halides to prepare original 3-ethoxypyrazoles. Synthesis 2015, 47, 511-516.
(5) Ermolenko, M. S.; Guillou, S.; Janin, Y. L. Pyrazole-3/5-carboxylic acids from 3/5-trifluoromethyl NH-pyrazoles. Tetrahedron 2013, 69, 257-263.
(6) Janin, Y. L. Preparation and chemistry of 3/5-halogenopyrazoles. Chem. Rev. 2012, 112, 3924-3958.
(7) Salanouve, E.; Retailleau, P.; Janin, Y. L. Few unexpected results from a Suzuki-Miyaura reaction. Tetrahedron 2012, 68, 2135-2140.
(8) Salanouve, E.; Guillou, S.; Bizouarne, M.; Bonhomme, F. J.; Janin, Y. L. 3-Methoxypyrazoles from 1,1-dimethoxyethene, few original results. Tetrahedron 2012, 68, 3165-3171.
(9) Guillou, S.; Bonhomme, F. J.; Ermolenko, M. S.; Janin, Y. L. Simple preparations of 4 and 5-iodinated pyrazoles as useful building blocks. Tetrahedron 2011, 67, 8451-8457.
(10) Guillou, S.; Janin, Y. L. 5-Iodo-3-ethoxypyrazoles, an entry point to new chemical entities. Chem. Eur. J. 2010, 16, 4669-4677.
(11) Guillou, S.; Bonhomme, F. J.; Chahine, D.; Nesme, O.; Janin, Y. L. N-arylation of 3-alkoxypyrazoles, the case of the pyridines. Tetrahedron 2010, 66, 2654-2663.
(12) Guillou, S.; Nesme, O.; Ermolenko, M. S.; Janin, Y. L. Carbon-4 arylation of 3-alkoxypyrazoles. Tetrahedron 2009, 65, 3529-3535.
(13) Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Nitrogen’s reactivity of various 3-alkoxypyrazoles. Tetrahedron 2009, 65, 2660-2668.
(14) Munier-Lehmann, H.; Vidalain, P.-O.; Tangy, F.; Janin, Y. L. On dihydroorotate dehydrogenases, their inhibitors and uses. J. Med. Chem. 2013, 56, 3148-3167.
(15) Munier-Lehmann, H.; Lucas-Hourani, M.; Guillou, S.; Helynck, O.; Zanghi, G.; Noel, A.; Tangy, F.; Vidalain, P. O.; Janin, Y. L. Original 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH). J. Med. Chem. 2015, 58, 860-877.
(16) Lucas-Hourani, M.; Munier-Lehmann, H.; El Mazouni, F.; Malmquist, N. A.; Harpon, J.; Coutant, E. P.; Guillou, S.; Helynck, O.; Noel, A.; Scherf, A.; Phillips, M. A.; Tangy, F.; Vidalain, P. O.; Janin, Y. L. Original 2-(3-alkoxy-1H-pyrazol-1-yl)azines inhibitors of human dihydroorotate dehydrogenase (DHODH). J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00606.
(17) Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Rev. 2007, 6, 29-40.
(18) Mayer, C.; Janin, Y. L. Non quinolone inhibitors of bacterial type IIA topoisomerases, a feat of bioisosterism. Chem. Rev. 2014, 114, 2313-2342.
(19) Bisacchi, G. S.; Manchester, J. I. A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. ACS Infect. Dis. 2015, 1, 4-41.
(20) Coutant, E. P.; Janin, Y. L. Synthetic accesses to coelenterazine and other imidazo[1,2-a]pyrazine-3-one luciferins, essential tools for bioluminescence-based investigations. 2015, Chem. Eur. J. doi:10.1002/chem.201501531.

 

Projects

CV

Yves L. Janin was born in 1965 in Paris, France. He studied chemistry initially at Bordeaux I and , then the Ecole Nationale Supérieure de Chimie de Paris and obtained a Ph.D. in organic chemistry in 1993, from the Pierre et Marie Curie University, Paris 6, under the guidance of Dr. Emile Bisagni at the Institut Curie. Following a year without any employment in science, he joined, for a two-year postdoc, Dr. David S. Grierson at the ICSN, Gif/Yvette, France. He then enjoyed a postdoctoral year in Professor Povl Krogsgaard-Larsen’s research laboratory at the Danish School of Pharmacy in Copenhagen. Following six years in the Institut Curie as a junior CNRS scientist, he went on a sabbatical year in Vitry/Seine Aventis research facilities before joining the Institut Pasteur in 2004. Throughout these years he has worked on various medicinal chemistry-driven designs and syntheses of heterocyclic derivatives concerning oncology, virology, neurobiology, and currently infectious diseases.

IsisWeb Author identifier number: N-5364-2014

Concerning  Medicinal Chemistry

For probably too long medicinal organic chemistry applications were underestimated, at least in the academic world, to provide solutions to plagues such as AIDS or hepatitis. However, the 95% cure achieved against hepatitis C as well as the daily cocktail of anti-HIV drugs taken by patients for up to decades are tributes to small organic molecules. Such successes are due to many factors starting with the extraordinary progresses made in life sciences. In fact, for a given disease, the modern techniques available in genomics, biochemistry and structural biology, have allowed the design of a wide range of relevant assays based on isolated protein targets all the way to whole cell constructs. With high-throughput screening (HTS) robots, these assays have been used to evaluate up to millions of small molecules. The compounds identified, also known as hits, were then the starting points of a lengthy process which ultimately led to a drug against the considered disease. Even if this process often fails to deliver a drug; it has many stages and the early ones are very relevant to the academic world interests. If a hit is usually of little use, optimized compounds can be of considerable interest in co-crystallization experiments for structural research or as probes to elucidate basic biological pathways in cells and even in vivo. This iterative chemical optimization process can thus be expected to provide a tool for cell-based studies, or better a lead, useful to achieve a proof of concept on a model animal. However, all too often, not even a valid1,2 tool emerges from such research. Reasons for this failure are still a matter of ongoing debates although the lack of original chemical entities available is often mentioned.3 Indeed, it is the confluence of the right assays and the right chemicals that has to be attained to achieve some success. This would be easy in a virtual world in which all the assays and all the molecules are available; in the real world,4 this requires luck and chemical libraries of good quality.

It is thus my belief that in the last 30 years, the speed of development of drug discovery sciences was not matched by how fast organic chemists could provide new chemical entities of interest. In many instances, the chemicals were not available for the considered assay (not to mention the chemists to undertake the optimization process). Indeed, there are still no methods to predict ex nihilo the potential of a given molecule nor ways to replace the know-how, insights and imagination of chemists. For this apparently simple reason, drug research has either turned to a substantial increase of the number of medicinal/organic chemists research teams, often as start-up companies and contract research organisations (CRO), or to the abandon of small molecules for the field of biologics. Only the future will tell on the pertinence of such choices. In any case, one contribution of the academic world to drug research remains the discovery and study of potential targets as well as valid chemicals tools effective on them. Moreover, the discovery of leads, effective on the considered in vivo model, should be an academic goal, ideally to find new drugs but also to establish proof of concepts and, in the process, train young scientists in medicinal chemistry.

 

 

(1) Baell, J.; Walters, M. A. Chemical con artists foil drug discovery. Nature 2014, 513, 481-483.

(2) Arrowsmith, C. H.; Audia, J. E.; Austin, C.; Baell, J.; Bennett, J.; Blagg, J.; Bountra, C.; Brennan, P. E.; Brown, P. J.; Bunnage, M. E.; Buser-Doepner, C.; Campbell, R. M.; Carter, A. J.; Cohen, P.; Copeland, R. A.; Cravatt, B.; Dahlin, J. L.; Dhanak, D.; Edwards, A. M.; Fredericksen, M.; Frye, S. V.; Gray, N.; Grimshaw, C. E.; Hepworth, D.; Howe, T.; Huber, K. V.; Jin, J.; Knapp, S.; Kotz, J. D.; Kruger, R. G.; Lowe, D.; Mader, M. M.; Marsden, B.; Mueller-Fahrnow, A.; Müller, S.; O’Hagan, R. C.; Overington, J. P.; Owen, D. R.; Rosenberg, S. H.; Roth, B.; Ross, R.; Schapira, M.; Schreiber, S. L.; Shoichet, B.; Sundström, M.; Superti-Furga, G.; Taunton, J.; Toledo-Sherman, L.; Walpole, C.; Walters, M. A.; Willson, T. M.; Workman, P.; Young, R. N.; Zuercher, W. J. The promise and peril of chemical probes. Nat. Chem. Biol. 2015, 11, 536-541.

(3) Macarron, R.; Banks, N. N.; Bojanic, D.; Burns, D. J.; Cirovic, D. A.; Garyantes, T.; Green, D. V.; Hertzberg, R. P.; Janzen, W. P.; Paslay, J. W.; Schopfer, U.; Sittampalam, G. S. Impact of high-throughput screening in biomedical research. Nat. Rev. Drug Discov. 2011, 10, 188-195.

(4) Rydzewski, M. R., Real world drug discovery. ed.; Elsevier: 2008.

 

 

 

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