Discovery of novel, highly potent and selective β-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles

• Published in: Bioorganic & medicinal chemistry 2006-12, Vol.14 (24), p.8396-8404
• Main Authors: DeMarco, Steven J., Henze, Heiko, Lederer, Alexander, Moehle, Kerstin, Mukherjee, Reshmi, Romagnoli, Barbara, Robinson, John A., Brianza, Federico, Gombert, Frank O., Lociuro, Sergio, Ludin, Christian, Vrijbloed, Jan Willem, Zumbrunn, Jürg, Obrecht, Jean-Pierre, Obrecht, Daniel, Brondani, Vincent, Hamy, François, Klimkait, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial Cationic Peptides - chemistry; Antineoplastic agents; Antiviral agents; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Calcium - metabolism; Chemokine CXCL12; Chemokines, CXC - metabolism; Chemokines, CXC - pharmacology; Chemotaxis - drug effects; CXCR4 inhibitor; Dogs; Drug Design; General aspects; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Leukemia - pathology; Medical sciences; Microsomes - drug effects; Molecular Mimicry; Oligopeptides - chemistry; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Peptide; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacokinetics; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; Protein Binding; Protein epitope mimetics; Protein Structure, Secondary; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, CXCR4 - antagonists & inhibitors; Tumor Cells, Cultured
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.09.003

Protein epitope mimetics (PEM) of Polyphemusin II act as highly potent CXCR4 inhibitors with good in vivo pharmacokinetic properties. Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring β-hairpin peptide polyphemusin II. The design involved incorporating important residues from polyphemusin II into a macrocyclic template-bound β-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.