Exploration of chemical space in search for new leads: cooperation with Boehringer-Ingelheim Pharma (2004–2015) and beyond

Within this cooperation we did planning, method development and synthesis of small combinatorial libraries of the representative target compounds. Novelty of scaffold, compliance with the Lipinski rule of five, and drug likeness had to be considered during the structure planning. The libraries provided by us would be further expanded by BI Pharma and tested for biological activity. Thus, we were involved as the contract partner in the R&D of new original drugs in this pharmaceutical company. Since the project was strongly structure-oriented, we now remember it as “The exploration of chemical space era”. The complete results of our endeavor has been published in a form of 20 original scientific papers. This vital experience toughened the group, which became highly experienced and skillful in terms of creative synthesis planning&execution as well as in terms of combinatorial, ‘click’, and ‘green’ chemistry.

The journey started in fall 2004, when we started to develop the synthesis of (2S,4S)-4-acyalminopyroglutamic carboxamides (JCC 2007). It was meant to be a “routine” one year project. In really it turned out to be a very tough project full of completely unexpected and unpredictable synthetic obstacles and it took us two years to finish it. However, we have learned several important lessons on practical target organic synthesis and since then we know much better how to avoid or bypass these “serendipity-born” problems. We also know that in multistep target synthesis there are no trivial transformations.

We then continued cooperation with a new topic: the pyrazole analogues of histamine. Several structural types comprised the direct analogues, where imidazole is simply replaced by the pyrazole, as well as cyclic, conformationally constrained analogues. (T 2007, JCC 2008, T 2009, S 2010, S 2011, HCA 2011, A 2012, M 2012, EJC 2013). The latter analogues represent a transition to the last topic, which were novel heterocyclic scaffolds have been planned and synthesized. Nine papers have been published on this topic (ACS Comb. Sci. 2012, S 2013-639, S 2013-3404, Mol. Divers. 2013, T 2014, S 2015, T 2015, JOC 2016, ACSi 2017). In diversity-oriented synthesis of polysubstituted dihydropyridine-3-carboxamides, the Suzuki-Miyaura arylation was critical step, where suitable reaction conditions could only be identified by combinatorial screening of 320 reaction conditions. Two hits were found, only one was really working (ACS Comb. Sci. 2012). Also the preparations of the first representatives of novel saturated bi- and tricyclic systems was tougher than expected. Thus, it took us almost a year to synthesize the first perhydropyrazolo[1,5-c]pyrimidines by a tedious 12-step synthesis (S 2013, 639). However, soon after, we came up with significantly shorter and combinatorial-friendly method (S 2013, 3404). In the synthesis of 3D rich heterocycles, the problem was scalability of the last step in a three-step literature procedure for the preparation of the key-intermediates. The only way to bypass this obstacle was to develop our own synthesis, which was scalable and reproducible (JOC 2016, 8920). In some instances, however, method development was flawless. Such example is parallel synthesis of analogues of anxiolytic drug Ocinaplon hypnotic-sedative drugs Zaleplon and Indiplon (Mol. Divers. 2013).

After the cooperation with BI Pharma was terminated in fall 2015, we carry on with prof. Marko Novinec from the biochemistry department of our faculty and in cooperation with the group of prof. Stanislav Gobec from the Faculty of pharmacy on the synthesis and biological evaluation of novel inhibitors of cathepsins (Bioorg. Chem. 2018), dihydroorotate dehydrogenase, butyrilcholine and acetylcholine esterase, and others.