A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity

Probing the Molecular Interactions between CXC Chemokine Receptor 4 (CXCR4) and an Arginine-Based Tripeptidomimetic Antagonist (KRH-1636)

“…35 and 1 inhibit binding of the same set of monoclonal antibodies, directed against the extracellular loops of CXCR4, it has been suggested that they have similar binding sites and molecular mode of action. 28,65 As Asp 171 , Asp 262 , and indirectly Glu 288 are also involved in binding of 1 (Figure 6), the present study confirms that these two compounds bind to the same receptor region.…”

“…28 and our own functional data validates 1 as a potent CXCR4 antagonist (EC 50 = 0.50 µM, Table 1) with respect to the endogenous ligand CXCL12. The phenyl-analog 5 (EC 50 = 8.5 µM) displayed 17-fold lower potency than 1, demonstrating an important role of the pyridine nitrogen in 1.…”

“…Design. The lead compound 1 was developed from a hit compound identified through screening of a chemical library, 28,29 and although recent patent literature discloses compounds related to 1, [25][26][27] no SAR data has been reported for this compound class. In order to confirm the importance of the functionalities in 1 that could be assumed to represent pharmacophoric groups, we first carried out a limited SAR study focusing on the two positively charged groups (R 1 and R 2 ) and the aromatic group (R 3 ) (Figure 2).…”

Potent Anti-R5 Human Immunodeficiency Virus Type 1 Effects of a CCR5 Antagonist, AK602/ONO4128/GW873140, in a Novel Human Peripheral Blood Mononuclear Cell Nonobese Diabetic-SCID, Interleukin-2 Receptor γ-Chain-Knocked-Out AIDS Mouse Model

“…Thus, one can say that the present model provides a greater reproducibility of high viremia levels than the mouse system reported by Koyanagi (14). It should be noted that the high levels of viremia and high engraftment rate achieved in this mouse model made it possible to monitor the changes in the viremia levels periodically in the same set of mice without sacrificing them, while most of the previously described SCID mouse models required mice to be sacrificed at each time point of testing (25,29,30) or needed further in vitro coculture of the PBMC recovered from the mice with freshly prepared uninfected target cells for an additional period of days (9,34). We demonstrated in this study that a novel SDP derivative, AK602, exerted highly potent activity against laboratory and primary R5 HIV-1 strains as well as MDR R5 HIV-1 variant with IC 50 values of subnanomolar concentrations (Table 1).…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…91 KRH-1636 is an orally available, non-peptide CXCR4 antagonist that inhibits infection by X4-HIV-1 virus and blocks responses to stimulation with CXCL12, such as calcium mobilization. 92 …”