Design and synthesis of peptide-based macrocyclic cyclophilin inhibitors.
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 Kd=5.4μM.
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. Electronic address: grangerba35@gmail.com.
Brett A
BA
Granger
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, USA. Electronic address: dean.brown@astrazeneca.com.
Dean G
DG
Brown
D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*
D047028:Macrocyclic Compounds; D010455:Peptides; D021983:Cyclophilins
Cyclophilin; Macrocycle; Peptidyl-prolyl isomerases; Ring-closing metathesis