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Cell permeability beyond the rule of 5
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Monash Univ, Dept Med Chem, MIPS, 381 Royal Parade, Parkville, Vic, Australia..
AstraZeneca, Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, SE-43183 Molndal, Sweden..
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
2016 (English)In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 101, 42-61 p.Article, review/survey (Refereed) PublishedText
Abstract [en]

Drug discovery for difficult targets that have large and flat binding sites is often better suited to compounds beyond the "rule of 5" (bRo5). However, such compounds carry higher pharmacokinetic risks, such as low solubility and permeability, and increased efflux and metabolism. Interestingly, recent drug approvals and studies suggest that cell permeable and orally bioavailable drugs can be discovered far into bRo5 space. Tactics such as reduction or shielding of polarity by N-methylation, bulky side chains and intramolecular hydrogen bonds may be used to increase cell permeability in this space, but often results in decreased solubility. Conformationally flexible compounds can, however, combine high permeability and solubility, properties that are keys for cell permeability and intestinal absorption. Recent developments in computational conformational analysis will aid design of such compounds and hence prediction of cell permeability. Transporter mediated efflux occurs for most investigated drugs in bRo5 space, however it is commonly overcome by high local intestinal concentrations on oral administration. In contrast, there is little data to support significant impact of transporter-mediated intestinal absorption in bRo5 space. Current knowledge of compound properties that govern transporter effects of bRo5 drugs is limited and requires further fundamental and comprehensive studies.

Place, publisher, year, edition, pages
2016. Vol. 101, 42-61 p.
Keyword [en]
Beyond the rule of 5, Permeability, Conformational shielding, Intramolecular hydrogen bonds, Macrocycles, Cyclic peptides, Efflux transporters, Quantitative structure permeability relationships
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-300382DOI: 10.1016/j.addr.2016.03.013ISI: 000378667800005PubMedID: 27067608OAI: oai:DiVA.org:uu-300382DiVA: diva2:951390
Carl Tryggers foundation AstraZeneca
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2016-08-08Bibliographically approved

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