Fluorinated Compounds in Medicinal Chemistry
The incorporation of a fluorinated substituent on a target molecule can alter many physicochemical (PC) and pharmacokinetic (PK) properties related to the design of therapeutics. For instance, fluorination typically alters hydrophilicity and lipophilicity, electrostatic and electronic properties, metabolic, thermal and oxidative stability, conformational rigidity, acid/base properties, and binding interactions between the small molecule and the biological target. Because of these perturbations, the ability to access fluorinated compounds is critical for developing new therapeutics and agrochemical agents.
Decarboxylative Strategies for Fluoroalkylation
Fluorinated Peptidomimetics for Delivering Peptides into the Central Nervous System
Endogenous opioid peptides regulate activity within the central nervous system (CNS), and are particularly interesting for treating pain, depression, and anxiety. Unfortunately, clinical use of peptide-based agents is restricted by poor physicochemical and biophysical properties, which limit penetration into the CNS. Therefore, many peptide-based probes cannot be employed clinically for treating many disease states.
To address this problem, the Altman group explores the use of fluorinated peptidomimetics (FPMs) to improve the drug-like properties of peptides, and to deliver peptides into the CNS. Recent efforts have provided rationally designed orally bioavailable FPM-based analogs of opioid peptides that cross the blood-brain-barrier. To access these unique target molecules, the group has developed new synthetic methods and strategies, which should be broadly applicable for accessing FPMs to address many disease states. The target FPM molecules are typically subjected to several in vitro and in vivo assays to evaluate pharmacodynamic, antinociception, distribution, metabolism, and pharmacokinetic properties. Data from the study will used to develop computational models to predict opioid activity and drug-like properties, which will facilitate the design of new analogs. This overarching strategy should be amenable for modulating physicochemical and biophysical properties of a broad spectrum of neuropeptides, with the ultimate goal of converting small peptide-based probes into CNS-active clinical candidates. To support this project, the Altman group collaborates with KU's Biotechnology Innovation and Optimization Center.
Regulating the Kynurenine Pathway
The kynurenine pathway (KP) regulates tryptophan metabolism and generates many modulatory biomolecules that in turn directly correlate to affect various aspects of neurotransmission, neurotoxicity, neuroprotection, inflammation, and other immunological functions. Further, dysregulation of this pathway directly correlates to many disease states, including neurological disorders, infectious diseases, and cancer, thus making small molecule modulators of the KP critical for understanding the diseases states, and for providing potential therapies.
Within this area, the Altman group works collaboratively to develop small molecule probes for studying and modulating enzymes in the kynurenine pathway. In some cases, these probes are used to study unique aspects of KP enzymology, while other efforts aim to develop small-molecule probes for modulating in vitro and in vivo models of various disease states. Long-term, these biological probes might serve as leads for downstream medicinal chemistry optimization. To support this project, the group actively collaborates with the research groups of Prof. Aimin Liu and Prof. Thomas Forsthuber, whose groups bring expertise in biochemistry and immunology to the project.