Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection.

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.

[Corporate Efforts to Research and Develop Therapeutic Agents for Infectious Diseases That Threaten Human].

Overcoming serious infectious diseases such as malaria, tuberculosis, and other neglected tropical diseases (NTDs) that threaten human life around the world is an important issue in global health. Most of these diseases are concentrated in developing and low-income countries, and in order to reinforce drug discovery activities, pharmaceutical companies are actively promoting industry-academia-government partnerships and utilizing funds to stimulate global health activities. In this presentation, three examples of our drug discovery activities are introduced. The first is participation in the Booster project led by Drugs for Neglected Diseases initiative (DNDi) aimed at creating therapeutic agents for leishmaniasis and Chagas disease, an effort supported by the Global Health Innovative Technology (GHIT) Fund. As domestic and overseas pharmaceutical companies participate in the project and provide their own compounds, it is possible to obtain structure-activity relationship information in a short period of time and improve compound potency. We collaborated with DNDi to create a lead compound from one hit compound, and contributed to further enhancement of its activity. The remaining two are collaborations with academia for the creation of new therapeutic agents or vaccines: a joint research project with Hokkaido University Research Center for Zoonosis Control for emerging viral diseases, and a collaboration with Nagasaki University in malaria. In each case, our researchers were based at the university, establishing close working collaborations with the university researchers. Novel solutions for serious infectious diseases are expected by the combination of the high-level basic research capabilities of academia and the drug discovery know-how and original compound libraries possessed by pharmaceutical companies.

Collaborative virtual screening to elaborate an imidazo[1,2-a]pyridine hit series for visceral leishmaniasis.

An innovative pre-competitive virtual screening collaboration was engaged to validate and subsequently explore an imidazo[1,2-a]pyridine screening hit for visceral leishmaniasis. In silico probing of five proprietary pharmaceutical company libraries enabled rapid expansion of the hit chemotype, alleviating initial concerns about the core chemical structure while simultaneously improving antiparasitic activity and selectivity index relative to the background cell line. Subsequent hit optimization informed by the structure-activity relationship enabled by this virtual screening allowed thorough investigation of the pharmacophore, opening avenues for further improvement and optimization of the chemical series.