Recent patents regarding the discovery of small molecule CXCR4 antagonists

Background: The chemokine receptors, CCR5 and CXCR4, are the primary co-receptors responsible for mediating HIV-1 cell entry. Small molecules that antagonize these receptors utilize a fundamentally different approach for controlling viral replication than most other classes of antiretroviral agents in that they act on host cell factors rather than viral enzymes. Although CCR5 modulators that demonstrate efficacy in the clinic against HIV have now become available, CXCR4 antagonist development is at present at a more nascent stage. Due to the ability of HIV to switch between CCR5 and CXCR4 entry co-receptors, the development of a CXCR4 antagonist is probably critical to prolonging the effectiveness of HIV therapies in patients. In addition, CXCR4 antagonists represent a novel class of drugs that could be used for the treatment of diseases other than HIV/AlDS. Objective: An overview of the most pertinent chemical classes that modulate the CXCR4 receptor, in addition to discussions of lead compound development. Methods: The review primarily covers patents and patent application publications filed in the past 8 years. However, earlier patents are included to provide a historical context. Results/conclusion: The early bicyclam class proved untenable for FIN treatment due to cardiotoxicity and lack of desirable pharmacokinetic properties. Second generation bicyclam mimics have the benefit of oral bioavailability but have, as yet, not proven successful in the clinic. The peptidomimetic analogues discussed capitalize on known receptor binding site interactions, which could lead to the development of potent and orally available CXCR4 antagonists.