Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration-Reference-Cited by-同舟云学术

Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration

Published:2024-07-12 Issue:28 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Pingitore Valeria¹²^ORCID,Pancholi Jessica¹^ORCID,Hornsby Thomas W.¹,Warne Justin¹,Pryce Gareth³,McCormick Laura J.⁴^ORCID,Hill Julia⁵,Bhosale Gauri⁵^ORCID,Peng Jing¹,Newton Lydia S.⁶^ORCID,Towers Greg J.⁶^ORCID,Coles Simon J.⁴^ORCID,Chan Ah Wing Edith¹^ORCID,Duchen Michael R.⁵^ORCID,Szabadkai Gyorgy⁵⁷^ORCID,Baker David³^ORCID,Selwood David L.¹^ORCID

Affiliation:

1. Drug Discovery, UCL Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.

2. Department of Biological and Health Sciences, Universidad Loyola Andalucía, Dos Hermanas, Seville 41704, Spain.

3. Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London E1 2AT, UK.

4. EPSRC National Crystallography Service, School of Chemistry, University of Southampton, Highfield Southampton SO17 1BJ, UK.

5. Department of Cell and Developmental Biology, UCL Consortium for Mitochondrial Research, London WC1E 6BT, UK.

6. Division of Infection and Immunity, University College London, London WC1E 6BT, UK.

7. Department of Biomedical Sciences, University of Padua, Padua 35131 Italy.

Abstract

Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.ado3501

Reference62 articles.

1. Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties

2. A. Talevi Central nervous system multiparameter optimization desirability in The ADME Encyclopedia: A Comprehensive Guide on Biopharmacy and Pharmacokinetics (Springer International Publishing 2021) pp. 1–8.

3. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1

4. Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

5. Toward the Design of Molecular Chameleons: Flexible Shielding of an Amide Bond Enhances Macrocycle Cell Permeability