Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Refine search result
1 - 4 of 4
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Doak, Bradley Croy
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Over, Bjorn
    Giordanetto, Fabrizio
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates2014In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 21, no 9, p. 1115-1142Article, review/survey (Refereed)
    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.

  • 2.
    Doak, Bradley
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Over, Bjorn
    Giordanetto, Fabrizio
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Macrocyclic drugs and clinical candidates - what are the limits of oral bioavailability?2014In: Abstracts of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Article in journal (Other academic)
  • 3.
    Over, Bjorn
    et al.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Molndal, Sweden..
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tyrchan, Christian
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Doak, Bradley C.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Foley, Michael A.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Triinst Therapeut Discovery Inst, New York, NY USA..
    Hilgendorf, Constanze
    AstraZeneca R&D Gothenburg, Safety & ADME Translat Sci, Drug Safety & Metab, Molndal, Sweden..
    Johnston, Stephen E.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Lee, Maurice D.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Lewis, Richard J.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    McCarren, Patrick
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Muncipinto, Giovanni
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Norinder, Ulf
    Swedish Toxicol Sci Res Ctr, Sodertalje, Sweden..
    Perry, Matthew W. D.
    Duvall, Jeremy R.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Structural and conformational determinants of macrocycle cell permeability2016In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, no 12, p. 1065-+Article in journal (Refereed)
    Abstract [en]

    Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 nonpeptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

  • 4.
    Poongavanam, Vasanthanathan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Doak, Bradley Croy
    Department of Medicinal Chemistry, MIPS, Monash University, Victoria, Australia.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space2018In: Current Opinion in Chemical Biology, ISSN 1367-5931, Vol. 44, p. 23-29Article, review/survey (Refereed)
    Abstract [en]

    Recent years have seen a dramatic increase in the number of drugs approved in chemical space outside of Lipinski’s rule of 5, that is in what has been termed beyond rule of 5 (bRo5) space. The development of three major classes of oral drugs that treat HIV and HCV infections and the growing evidence that novel, difficult targets can be accessed has prompted research into understanding design of drugs displaying cell permeability, solubility and ultimately oral bioavailability in bRo5 space. Studies have found a consistent outer property limit for a reasonable chance of de novo designing oral bioavailability. In addition, several property-based guidelines, along with incorporation of chameleonic features, have emerged as strategies to aid design in bRo5 space. A more detailed understanding of the complex and environment dependent conformational landscape will likely be the focus of the next generation of guidelines allowing property predictions of ever more complex compounds. By pushing the boundaries of current orally designable chemical space we hope that discoveries will be made for fundamental science and also for discovery of novel therapeutics.

1 - 4 of 4
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf