92369 - Molecular Modification Strategies towards Pharmacokinetic Optimization in Drug Discovery and Development

Learning outcomes

The course deals with the relationships between the structural aspects of bioactive compounds and the mainly processes related to the pharmacokinetic phase, i.e. absorption, distribution, metabolism and excretion, pointing the principal physicochemical properties that could be adjusted during the optimization of an orally-active drug candidate and the different strategies used to do it.

Course contents

Drug dosing: The pharmaceutical phase

Definition of pharmaceutical phase and its steps. Characterization of the importance of an adequate water solubility profile of drugs for the pharmaceutical phase. Definition of the structural reasons of a poor water solubility. Strategies used to improve the solubility of lead-compounds: salt formation, introduction of polar or ionizable subunits, broken of planarity of flat compounds.

Physicochemical properties of drug candidates

Lipophilicity (Log P) and ionization constant (pKa): fundamentals and effects. Determination and analysis of Hansch’s hydrophobicity constants of functional groups. Determination and analysis of Hammett’s electronic constants of functional groups. The structural aspects that influence the pKa of acids and bases: The example of piroxicam. Applications and limitations of the rules for the rapid assessment of drug-like properties. Structure modification strategies for optimization of the lipophilicity and pKa.

The pharmacokinetic phase

Permeability: Fundamentals and effects on bioavailability. Permeability structure modification strategies: changing an ionizable group; adding lipophilicity; isosteric replacement of polar groups; reducing hydrogen bonding; prodrugs, etc. Modifying absorption and excretion of drugs through transporters. The effects of the structure and chirality on plasma protein binding profile. Strategies of molecular modification to improve the metabolic and plasmatic stability of drug candidates: protecting vulnerable sites by substitution or steric hindrance. Structural characteristics of mainly CYP isoforms substrates. CYP inhibition: fundamentals and importance for drug-drug interactions. Structure modification strategies to reduce CYP inhibition: case studies. The impact of hERG blocking in drug discovery. SAR of hERG blocking: structure modification strategies to avoid hERG modulation.

Readings/Bibliography

Kerns, E. H.; Di, L. Drug-like Properties: Concepts, structure design and methods, Academic Press: Amsterdan, 2008, pp. 1-214.

Wermuth, C.-G. The Practice of Medicinal Chemistry, Part VI, Academic Press: Oxford, 2008, pp. 635-852.

Di, L.; Fish, P. V.; Mano, T. Bridging solubility between drug discovery and development. Drug Discovery Today 17, 486-495, 2011.

Lipinski, C. A. Lead- and drug-like compounds: The rule of five revolution. Drug Discovery Today: Technologies 1, 337-341, 2004.

Gleeson, M. P.; Hersey, A.; Montanari, D.; Overington, J. Probing the links between in vitro potency, ADMET and physicochemical parameters. Nature Reviews in Drug Discovery 10, 197-208, 2011.

Yang, Y.; Engkvist, O.; Llinas, A.; Chen, H. Beyond size, ionization state, and lipophilicity: Influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds. Journal of Medicinal Chemistry 55, 3667-3677, 2012.

Lewis, D. F. V.; Dickins, M. Substrate SARs in human P450s. Drug Discovery Today 7, 918-925, 2002.

Ishikawa, M., Hashimoto, Y. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. Journal of Medicinal Chemistry 54, 1539-1554, 2011.

Ritchie, T. J.; Macdonald, S. J. F. Heterocyclic replacements for benzene: Maximising ADME benefits by considering individual ring isomers. European Journal of Medicinal Chemistry 124, 1057-1068, 2016.

Gunaydin, H.; Altman, M. D.; Ellis, J. M.; Fuller, P.; Johnson, S. A.; Lahue, B.; Lapointe, B. Strategy for extending half-life in drug design and its significance. ACS Medicinal Chemistry Letters 9, 528-533, 2018.

Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl bioisostere: Examining the “lipophilic hydrogen bond donor” concept. Journal of Medicinal Chemistry 60, 797-804, 2017.

Teaching methods

Lectures in class

Teaching tools

Videoprojector, PC

Office hours

See the website of Carlos Alberto Manssour Fraga