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Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
2014 (English)In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 21, no 9, 1115-1142 p.Article, review/survey (Refereed) Published
Abstract [en]

The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compounds with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.

Place, publisher, year, edition, pages
2014. Vol. 21, no 9, 1115-1142 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-235855DOI: 10.1016/j.chembiol.2014.08.013ISI: 000342626700010OAI: oai:DiVA.org:uu-235855DiVA: diva2:762527
Available from: 2014-11-12 Created: 2014-11-11 Last updated: 2017-12-05Bibliographically approved

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Doak, Bradley CroyKihlberg, Jan

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