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Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties?
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 2, 278-95 p.Article in journal (Refereed) Published
Abstract [en]

Macrocycles are ideal in efforts to tackle "difficult" targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 √Ö(2). Moreover, insight from a group of "de novo designed" oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space.

Place, publisher, year, edition, pages
2014. Vol. 57, no 2, 278-95 p.
National Category
Natural Sciences
Research subject
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-240933DOI: 10.1021/jm400887jPubMedID: 24044773OAI: oai:DiVA.org:uu-240933DiVA: diva2:777290
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2017-12-05

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Kihlberg, Jan

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