Recent patents regarding the discovery of small molecule CXCR4 antagonists.
BACKGROUND
The chemokine receptors, CCR(5) and CXCR(4), 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 CCR(5) modulators that demonstrate efficacy in the clinic against HIV have now become available, CXCR(4) antagonist development is at present at a more nascent stage. Due to the ability of HIV to switch between CCR(5) and CXCR(4) entry co-receptors, the development of a CXCR(4) antagonist is probably critical to prolonging the effectiveness of HIV therapies in patients. In addition, CXCR(4) antagonists represent a novel class of drugs that could be used for the treatment of diseases other than HIV/AIDS.


OBJECTIVE
An overview of the most pertinent chemical classes that modulate the CXCR(4) 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.


CONCLUSIONS
The early bicyclam class proved untenable for HIV 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 CXCR(4) antagonists.
Department of Chemistry, Emory University, 1521 Dickey Drive, Atlanta, GA 30322, USA.
Cara A
CA
Mosley
Lawrence J
LJ
Wilson
John M
JM
Wiseman
Jason W
JW
Skudlarek
Dennis C
DC
Liotta
D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy* / Q000503:physiopathology; D015497:HIV-1 / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D010330:Patents as Topic; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor