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Why (not) macrocycles in drug discovery?
Abstract: Macrocycles are attracting major interest in drug discovery as one of a few new chemical modalities that can bridge the gap between small molecule drugs and biologics. Macrocyclization may improve both binding affinity and selectivity for targets that have large, flat or groove shaped binging sites. In addition, cyclization is often suggested to have a favorable impact on essential drug properties such as membrane permeability, metabolic stability, and overall pharmacokinetics. In this presentation, I will discuss the evidence supporting the use of macrocycles in drug discovery, while highlighting that this is not always black and white. I will also briefly discuss one of the main drawbacks of macrocycles – their synthetic complexity. |
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Related publications:
Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties?, F. Giordanetti, J. Kihlberg, J. Med. Chem. 2014, 57, 2, 278–295.
Structural and conformational determinants of macrocycle cell permeability, B. Over, P. Mattson, C. Tyrchan, P. Artursson, B. C. Doak, M. A. Foley, C. Hilgendorf, S. E. Johnston, M. D. Lee IV, R. J. Lewis, P. McCarren, G. Muncipinto, U. Norinder, M. W. D. Perry, J. R. Duvall, J. Kihlberg. Nat. Chem. Biol. 2016, 13, 106-1074.
Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs, E. Danelius, V. Poongavanam, S. Peitner, L. H. E. Wieske, M. Erdelyi, J. Kihlberg, Chem. Eur. J. 2020, 23, 5231-5244.
Mining Natural Products for Macrocycles to Drug Difficult Targets, F. Begnini, V, Poongavanam, B. Over, M. Castaldo, S. Geschwinder, P. Johansson, M. Tyagi, C. Tyrchan, L. Wissler, P. Sjöö, S. Scheisser, J. Kihlberg, J. Med. Chem, 2016, 64, 2, 1054–1072.
Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties?, F. Giordanetti, J. Kihlberg, J. Med. Chem. 2014, 57, 2, 278–295.
Structural and conformational determinants of macrocycle cell permeability, B. Over, P. Mattson, C. Tyrchan, P. Artursson, B. C. Doak, M. A. Foley, C. Hilgendorf, S. E. Johnston, M. D. Lee IV, R. J. Lewis, P. McCarren, G. Muncipinto, U. Norinder, M. W. D. Perry, J. R. Duvall, J. Kihlberg. Nat. Chem. Biol. 2016, 13, 106-1074.
Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs, E. Danelius, V. Poongavanam, S. Peitner, L. H. E. Wieske, M. Erdelyi, J. Kihlberg, Chem. Eur. J. 2020, 23, 5231-5244.
Mining Natural Products for Macrocycles to Drug Difficult Targets, F. Begnini, V, Poongavanam, B. Over, M. Castaldo, S. Geschwinder, P. Johansson, M. Tyagi, C. Tyrchan, L. Wissler, P. Sjöö, S. Scheisser, J. Kihlberg, J. Med. Chem, 2016, 64, 2, 1054–1072.
