Identification of spirocyclic or phosphate substituted quinolizine derivatives as novel HIV-1 integrase inhibitors: a patent evaluation of WO2016094197A1, WO2016094198A1 and WO2016154527A1

ABSTRACT

Introduction: Highly active antiretroviral therapy (HAART) has been widely adopted to control the HIV-1 infection successfully. HIV-1 integrase (IN) inhibitors are primary drugs in HAART regimens targeting integration step in the HIV-1 life cycle. However, due to the emergence of viral resistance and cross-resistance amongst drugs, there is a pressing need for new and potent IN inhibitors. This review covers the three patents describing spirocyclic and phosphate substituted quinolizine derivatives as novel HIV-1 IN inhibitors for the discovery of new anti-HIV-1 drug candidates.

Areas covered: This review is focused on spirocyclic and phosphate substituted quinolizine derivatives bearing the same metal chelation scaffold as novel HIV-1 IN inhibitors.

Expert opinion: Generally, privileged structure-based optimizations have emerged as an effective approach to discover newly antiviral agents. More generally, due to the similar Mg²⁺ catalytic active centers of endoribonucleases, some divalent metal ion chelators were found to be versatile binders targeting multiple metalloenzymes. Therefore, privileged structure-based scaffold re-evolution is an important tactic to identify new chemotypes, to explore unknown biological activities, or to provide effective ligands for multiple targets by modifying the existing active compounds.

KEYWORDS:

• AIDS
• HIV-1
• IN inhibitors
• prodrug
• privileged structure
• drug design

Article highlights

• There is an urgent demand for developing new HIV-1 IN inhibitors with high anti-resistance activities, improved physicochemical properties and low side effects.

• This review covers the three patents describing spirocyclic and phosphate substituted quinolizine derivatives bearing the same metal chelation scaffold as novel HIV-1 IN inhibitors for the discovery of new anti-HIV-1 drug candidates.

• Acetal carbonate prodrug approach is a new tactic to enhance oral absorption and improve drug potency of anti-HIV drug candidates, which could mask the negative charges of predecessor successfully via introducing carbonate acetal promoiety.

• The privileged structure-derived modification, via prodrug, bioisosterism, scaffold hopping, etc., is an important approach for seeking novel anti-HIV agents.

• Privileged structure-based scaffold re-evolution is an important tactic to identify new chemotypes, to explore unknown biological uses, or to provide effective ligands for multiple targets by modifying the existing active compounds.

This box summarizes key points contained in the article.

Declaration of interest

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 funded by Key Project of NSFC for International Cooperation grant number 81420108027, Major Project of Science and Technology of Shandong Province grant number 2015ZDJS04001, National Natural Science Foundation of China grant number 81573347 and Young Scholars Program of Shandong University grant number 2016WLJH32.