Central Nervous System Multiparameter Optimization Desirability

Talevi, Alan

doi:10.1007/978-3-030-51519-5_150-1

Cited by 2 publications

(1 citation statement)

References 10 publications

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“…Small molecule drugs are usually designed to transmit the blood-brain barrier by diffusion across the cell membranes and this has led to several descriptions of CNS drug-like space and optimization rules or algorithms (1). In general, optimal CNS small molecule drug space is thought to be characterized by low molecular weight, low polarity, and high permeability, though a robust predictive model is still elusive (2). CNS drug-like space is regarded as smaller than the original concept of drug-likeness described by Lipinski (rule of five) (3) and the expanded beyond ruleof-five (bRo5) concept which considers many natural products and more modern drugs (4).…”

Section: Introductionmentioning

confidence: 99%

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

Pingitore,

Pancholi,

Hornsby

et al. 2024

Sci. Adv.

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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.

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Section: Introductionmentioning

confidence: 99%