CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

ABSTRACT

Introduction: The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists.

Areas covered: This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies.

Expert opinion: The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.

KEYWORDS:

• CCR5
• CCR2
• CXCR4
• Maraviroc
• HIV
• entry inhibitors
• antagonists
• Cenicriviroc
• chemokine receptors

Article highlights

• A brief background is provided on CCR5 receptor biology and pharmacology, the dual-tropism behavior of HIV (R5/X4), and the significance of the δ-32 deletion leading into the introduction of CCR5 entry inhibitors.

• A short review on the clinical outcomes of the first generation CCR5 antagonists is presented with a focus on the only FDA approved drug in this class - Maraviroc.

• A thorough review of the drug discovery and research efforts on second-generation CCR5 antagonists is provided identifying various drug scaffolds, preclinical and clinical candidates including PF-232798 and INCB9471.

• The discovery of dual-chemokine (CCR5 and CCR2 or CXCR4) antagonists is discussed culminating with the identification of the dual CCR5/CCR2 antagonist TAK-652/Cenicriviroc as the most advanced candidate currently in Phase II trials.

• A final examination of the upside potential, challenges and future for CCR5 antagonist development for HIV is provided. This includes the expanded role of Maraviroc in curbing immunologic and metabolic disorders, the challenges with the tropism test, the emergence of dual chemokine receptor pharmacology, drug-bound receptor resistance development, and use in non-HIV applications.

This box summarizes key points contained in the article.

Declaration of interest

K. Giesler has received funding support from The Emory University. M. Kim, L. Wilson, D. Liotta, Y. Tahirovic and V. Truax have received post-doctoral support from Bristol-Myers Squibb. D. Liotta has also received NIH funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.