Design and synthesis of peptide-based macrocyclic cyclophilin inhibitors

Brett A Granger; Dean G Brown

doi:10.1016/j.bmcl.2016.09.039

Design and synthesis of peptide-based macrocyclic cyclophilin inhibitors

Bioorg Med Chem Lett. 2016 Nov 1;26(21):5304-5307. doi: 10.1016/j.bmcl.2016.09.039. Epub 2016 Sep 15.

Authors

Brett A Granger¹, Dean G Brown²

Affiliations

¹ Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. Electronic address: grangerba35@gmail.com.
² Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. Electronic address: dean.brown@astrazeneca.com.

PMID: 27687672
DOI: 10.1016/j.bmcl.2016.09.039

Abstract

The efficient assembly of an 18-membered macrocyclic peptide core was realized by a straightforward and convergent approach utilizing ring-closing metathesis of the corresponding linear tetrapeptides as the key transformation. This approach allowed for the facile preparation of a focused library of novel macrocycles that culminated in the discovery of a cyclophilin A inhibitor with a K_d=5.4μM.

Keywords: Cyclophilin; Macrocycle; Peptidyl-prolyl isomerases; Ring-closing metathesis.

MeSH terms

Cyclophilins / antagonists & inhibitors*
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / pharmacology*
Peptides / chemistry*

Substances

Macrocyclic Compounds
Peptides
Cyclophilins