Discovery of novel, highly potent and selective beta-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles.
Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring beta-hairpin peptide polyphemusin II. The design involved incorporating important residues from polyphemusin II into a macrocyclic template-bound beta-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized in iterative cycles, resulting in the CXCR4 inhibitors POL2438 and POL3026. The inhibitory potencies of these compounds were confirmed in a series of HIV-1 invasion assays in vitro. POL3026 showed excellent plasma stability, high selectivity for CXCR4, favorable pharmacokinetic properties in the dog, and thus has the potential to become a therapeutic compound for application in the treatment of HIV infections (as an entry inhibitor), cancer (for angiogenesis suppression and inhibition of metastasis), inflammation, and in stem cell transplant therapy.
DeMarco
Steven J
SJ
Chemistry Department, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Henze
Heiko
H
Lederer
Alexander
A
Moehle
Kerstin
K
Mukherjee
Reshmi
R
Romagnoli
Barbara
B
Robinson
John A
JA
Brianza
Federico
F
Gombert
Frank O
FO
Lociuro
Sergio
S
Ludin
Christian
C
Vrijbloed
Jan Willem
JW
Zumbrunn
Jürg
J
Obrecht
Jean-Pierre
JP
Obrecht
Daniel
D
Brondani
Vincent
V
Hamy
François
F
Klimkait
Thomas
T
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000473:pathology; D008861:Microsomes / Q000187:drug effects; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D023181:Antimicrobial Cationic Peptides; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D009842:Oligopeptides; C516699:POL2438 peptide; C516700:POL3026 peptide; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; C062386:polyphemusin II; D002118:Calcium