Ateneo - UPO

The module aims to provide a practical overview of the role of medicinal chemistry in the development of small molecules and new chemical modalities, with particular attention to the advancement of a preclinical candidate toward the clinical stage.
The chemical-pharmaceutical criteria guiding the selection of a preclinical candidate will be discussed, including drug-like properties, ADME/PK profile, and synthetic developability. The course will also address the fundamental principles of process chemistry, with particular reference to the robustness, safety, yield, and sustainability of the synthetic route.
Part of the module will be dedicated to the characterization of the active pharmaceutical ingredient, considering the identity, purity, and stability of the API, together with the identification and control of the main impurities. Finally, the opportunities and key development challenges associated with emerging chemical modalities and advanced medicinal chemistry strategies will be discussed, with a focus on targeted degradation approaches, such as PROTACs and molecular glues, antibody–drug conjugates (ADCs), peptidic and non-peptidic macrocycles, and deuterated drugs. Through the analysis of approved drugs and candidates in advanced preclinical or clinical development, the course aims to promote a critical and multidisciplinary approach to pharmaceutical development. It will also strengthen students’ ability to retrieve, assess, and communicate scientific information, including information obtained using artificial intelligence tools.

• Teaching materials provided during the course
• Scientific literature
• Selected ICH guidelines, in particular:
ICH Q3A(R2) – Impurities in New Drug Substances
ICH M7(R2) – Mutagenic Impurities
ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
ICH Q11 – Development and Manufacture of Drug Substances
• N. G. Anderson, Practical Process Research and Development, Academic Press

At the end of the module, students will have acquired knowledge of the role of practical medicinal chemistry in advancing a preclinical candidate toward the clinical stage. They will understand the chemical-pharmaceutical criteria that guide the selection and development of a candidate. They will also become familiar with the fundamental principles of process chemistry, non-GMP/GMP synthesis, API characterization, and impurity control.

Attendance of the third-year course in Medicinal Chemistry 1.

The innovative teaching activities will include:
• analysis and discussion of case studies;
• group work.
As part of the group activities, students may use artificial intelligence tools to support the collection and organization of information and the preparation of the final case study.
Particular attention will be devoted to the critical verification of the information obtained, through consultation of the scientific literature, regulatory sources and, where relevant, patent literature. The activities will be carried out in alignment with the objectives of the multidisciplinary course “Drug Discovery and Development” and will be aimed at preparing the case study that will be the subject of the final assessment, with particular reference to the advancement of a preclinical candidate toward the clinical stage.

Students with physical disabilities, Learning Disabilities or Special Education Needs can request specific services and tools via the Staff Sviluppo e Coordinamento Carriere e Servizi alle Studentesse e agli Studenti, consulting the University webpage: https://www.uniupo.it/en/services/services-students-physical-or-learning-disabilities
Students with disabilities, learning disabilities or special education needs, once they have contacted the University Staff, can refer to the tutor in charge of the course to define the examination modalities, concerning academic aspects.

Assessment of learning outcomes will take place as part of the integrated final examination for the Drug Discovery and Development course. The examination will consist of two components.
Written examination. The written examination will be common to all modules of the course and will be designed to assess students’ knowledge and understanding of the theoretical content covered during the course. The written examination will account for 60% of the final grade. The written examination grade will be calculated as the weighted average of the marks obtained in the individual course modules.
Oral presentation of a case study. Students will develop and present a multidisciplinary case study related to the Drug Discovery and Development process. The presentation will take place on the final day of the course and will assess students’ ability to integrate the knowledge acquired across the different disciplinary areas covered by the course. When preparing their work, students may use generative artificial intelligence tools to support information retrieval and processing. During the presentation, they will be required to explain how these tools were used, which information was subsequently verified, and how the tools contributed to the development of the work.
The oral presentation will account for 40% of the final grade.

Assessment criteria
The overall assessment will take into account:
1. knowledge and understanding of the subject-specific content;
2. ability to integrate knowledge and skills acquired across the different course modules;
3. ability to apply knowledge to realistic problems related to drug development;
4. independent judgement and critical analysis skills;
5. appropriate use of scientific and technical language;
6. quality of the presentation and argumentation;
7. ability to use and critically discuss the information sources consulted in the preparation of the case study.

The module will address the role of practical medicinal chemistry in advancing a preclinical candidate toward the clinical stage, with particular attention to the assessment of the chemical, synthetic, and physicochemical developability of the molecule.
The criteria used to evaluate a drug candidate beyond biological activity alone will be discussed, including drug-like properties, ADME/PK profile, and synthetic tractability. It will be emphasized that a molecule with promising pharmacological activity is not necessarily suitable for development if it presents limitations in terms of solubility, permeability, stability, synthetic scalability, or impurity control. The course will then introduce the transition from exploratory laboratory synthesis to development synthesis, with a focus on route selection, process chemistry, and scale-up. Topics will include the choice of the synthetic route, reduction of the number of synthetic steps, overall yield, robustness and reproducibility of the process, safety of reagents and intermediates, solvent selection, isolation of intermediates, purification strategies alternative to chromatography, and process sustainability. Part of the module will be dedicated to the production and control of the selected candidate, distinguishing between non-GMP and GMP synthesis according to the different stages of preclinical and clinical development. The principles of API characterization will be addressed, including identity, purity, stability, residual solvents, elemental impurities, process-related impurities, and potential mutagenic impurities.
The opportunities and main challenges associated with new chemical modalities and advanced medicinal chemistry strategies will also be discussed. Particular attention will be devoted to protein degraders, such as PROTACs and molecular glues, and to antibody–drug conjugates (ADCs), which, although they include small-molecule components, display physicochemical, pharmacological, and developability features that differ from those of traditional drugs.
Finally, the module will include examples related to covalent inhibitors, peptidic and non-peptidic macrocycles, and deuterated drugs, highlighting how each class of molecules requires specific criteria for design, optimization, and development. In the context of deuterated drugs, deuterium-switch approaches and de novo design strategies will be discussed, with particular attention to the effects of deuterium incorporation on metabolic stability, physicochemical properties, selectivity/specificity, and toxicity. The different topics will be integrated through the analysis and discussion of case studies, also supporting the preparation of the final case study planned within the multidisciplinary course.

Knowledge and understanding. At the end of the module, students will have acquired knowledge of the role of practical medicinal chemistry in advancing a preclinical candidate toward clinical development. They will understand the medicinal chemistry and pharmaceutical development criteria that guide candidate selection and progression. They will also be familiar with the fundamental principles of process chemistry, non-GMP and GMP synthesis, API characterization, and impurity control.
Applying knowledge and understanding. Students will be able to critically assess the developability of a preclinical candidate by integrating physicochemical properties, ADME/PK profile, and synthetic tractability. They will be able to recognize the main challenges associated with the transition from exploratory synthesis to development synthesis, considering the robustness of the synthetic route, safety, yield, sustainability, scalability, and quality of the active pharmaceutical ingredient. They will also be able to apply these concepts to the analysis/study of small molecules, including deuterated drugs, and new chemical modalities in Drug Discovery and Development.
Making judgements. Students will be able to critically analyze documents and information related to drugs already on the market, in advanced preclinical development, or in clinical development, with particular attention to chemical-pharmaceutical aspects. They will also be able to integrate different scientific sources, including primary, secondary, and grey literature, while critically assessing the reliability, quality, and relevance of the information retrieved, including information generated using artificial intelligence tools.
Communication skills. Students will have strengthened their scientific communication skills, adapting their language according to the nature of the audience. They will be able to clearly and rigorously present the chemical-pharmaceutical challenges associated with the development of a drug candidate and contribute to the preparation of an effective pitch within the framework of the multidisciplinary case study.
Learning skills. The course will provide conceptual tools useful for understanding pharmaceutical development activities carried out in an industrial setting and for addressing advanced topics related to the design, optimization, and industrialization of medicinal products. The ability to use innovative tools responsibly and consciously for the acquisition and processing of scientific information will also be encouraged.